
==== Front
Contemp Clin Trials Commun
Contemp Clin Trials Commun
Contemporary Clinical Trials Communications
2451-8654
Elsevier

S2451-8654(24)00106-6
10.1016/j.conctc.2024.101359
101359
Article
Prevention of postpartum methamphetamine use with micronized progesterone trial (PROMPT): A pilot randomized controlled trial protocol☆
Smid Marcela C. Marcela.Smid@hsc.utah.edu
ab⁎
Seliski Natasha bc
Charles Jasmin E. ab
Castro Stephanie b
Humiston Grace E. b
Cash Elysha b
Allshouse Amanda a
Turner Elizabeth a
Carlston Kristi b
Gibson Marie e
Gordon Adam J. bd
Cochran Gerald T. bd
a Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah Health, 30 N. Mario Capecchi Drive, Floor 5 South, Salt Lake City, UT, USA
b Program for Addiction Research, Clinical Care, Knowledge and Advocacy (PARCKA), Division of Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, 295 Chipeta Way, Salt Lake City, UT, USA
c Department of Family and Preventive Medicine, University of Utah School of Medicine, 375 Chipeta Way Suite A, Salt Lake City, UT, USA
d Informatics, Decision-Enhancement, and Analytic Sciences Center (IDEAS), Salt Lake City VA Health Care System, Salt Lake City, UT, USA
e Utah Population Database, University of Utah Huntsman Cancer Institute, 2000 Circle of Hope Drive, Salt Lake City, UT, USA
⁎ Corresponding author. Department of Obstetrics and Gynecology, University of Utah Health, 30 N. Mario Capecchi Drive, Floor 5 South, Salt Lake City, UT, USA. Marcela.Smid@hsc.utah.edu
30 8 2024
10 2024
30 8 2024
41 10135911 2 2024
1 8 2024
28 8 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Background

While most pregnant individuals with methamphetamine use disorder (MUD) achieve abstinence, the postpartum period remains a vulnerable time for return to methamphetamine use (MU). Promising data from human and animal models, including three randomized controlled trials, suggest that micronized progesterone may prevent postpartum return to cocaine and nicotine use by reducing cravings. The primary objective of this study is to assess feasibility of enrollment and randomization of postpartum individuals with MUD to micronized progesterone to prevent return to MU. The secondary objectives are to evaluate safety, establish a preliminary estimate of efficacy, and characterize the association between allopregnanolone levels and methamphetamine cravings.

Methods

This is a pilot double-blind placebo randomized controlled trial. We plan to enroll 40 postpartum individuals with MUD over 24-months. Individuals, stratified by opioid use disorder (OUD), are randomized 1:1–400 mg oral micronized progesterone daily or placebo and attend weekly study sessions for 12 weeks. Feasibility is measured by achieving 80 % of enrollment goal. Safety is evaluated by side effect frequency, mental health status changes, lactation and medical complications. Efficacy is assessed by comparing proportion of participants with return to MU and time to return to MU based on self-report or urine testing between treatment and control groups. Salivary allopregnanolone levels and methamphetamine cravings are compared between the groups.

Conclusion

Study results will provide a first critical step towards potential intervention for prevention of return to MU among postpartum individuals. Completion of this trial will set the stage for a large-scale efficacy trial.

Clinical trial registration number: NCT 05128071.

Keywords

Postpartum period
Methamphetamine
Substance use disorder
Progesterone
Randomized controlled trial
==== Body
pmc1 Background

Methamphetamine use (MU) among pregnant and postpartum people has continued unabated for over a decade in the United States with prevalence rates ranging from 0.17 to 1 % [[1], [2], [3]]. Peripartum individuals with methamphetamine use disorder (MUD) have a one in five chance of severe maternal morbidity and mortality through the year postpartum [4]. Nationwide, pregnancy-associated psychostimulant overdose deaths, defined as deaths in pregnancy and one year postpartum, have more than doubled from 2017 to 2020 [5]. The peripartum period is a particularly vulnerable time for those with methamphetamine and other substance use disorders (SUD) with a high risk of return to use and overdose postpartum [6]. Factors associated with high rates of return to use include co-occurring SUD and mental health condition destabilization, child custody removal and limited social support [[7], [8], [9], [10], [11]].

A hypothesized contributor to high risk of return to use postpartum is the role of peripartum hormonal changes and their effect on cravings during the peripartum period [12]. Human and animal studies indicate that high levels of progesterone (luteal phase of menses, pregnancy) are associated with decreased frequency of drug-seeking behaviors, fewer stimulant award and cravings effects compared to times of low progesterone levels (follicular phase of menses, postpartum period) [[13], [14], [15], [16]]. Leveraging the idea that exogenous progesterone administration can decrease return to use and cravings among postpartum individuals, three randomized clinical trials showed promising results in the use of micronized progesterone for prevention of return to tobacco [17,18] and cocaine use [19]. The underlying proposed mechanism is that micronized progesterone metabolizes into allopregnanolone, a neurosteroid that regulates neuronal signaling including gamma-aminobutyric-acid (GABA) transmission enhancement to attenuate drug reward [20,21]. These findings suggest exogenous progesterone as a possible intervention among postpartum persons with MUD to prevent return to use. No prior studies have assessed the progesterone as an intervention to prevent MU or decrease methamphetamine cravings.

1.1 Study aims

The primary objective of this study is to assess feasibility of enrollment and randomization of postpartum individuals with MUD to micronized progesterone to prevent return to MU. The secondary objectives are to evaluate safety and preliminary estimate of efficacy. Additionally, we will characterize the association between allopregnanolone levels and methamphetamine cravings. The rationale for this objective is: 1) many participants may be recruited from SUD treatment facilities where return to use is typically low and 2) craving, a criterion of active MUD, potentially increasing risk of return to use, particularly among postpartum individuals [21,22].

2 Methods

2.1 Study design

This double-blind placebo randomized controlled trial (RCT) builds on the protocol reported by Yonkers et al [19]. Participants will be randomized 1:1 to either micronized progesterone (200 mg twice daily) or placebo (Fig. 1), stratified by OUD. We plan to enroll 40 postpartum individuals with MUD over a 24-month timeframe who have discontinued MU for at least four weeks. Data collection will occur at baseline and weekly for 12 weeks. Reporting of the study will follow CONSORT guidelines and the SPIRIT checklist can be accessed as a supplemental file (Appendix A). This study and protocol (version 3.1, updated 4/26/2023) is approved by the University of Utah Institutional Review Board and is registered with ClinicalTrials.gov (NCT 05128071).Fig. 1 Study flowchart. Data collection at baseline and follow-up visits.

Fig. 1

2.2 Study participants

Participants will be postpartum individuals within 12 weeks end of pregnancy (miscarriage, stillbirth, abortion, or live birth) and have no MU for four or more weeks as the theorized mechanism of action of exogenous progesterone is stabilize the amygdala, thereby reducing cravings and preventing return to MU. We selected this timeframe because allopregnanolone and progesterone levels return to pre-pregnancy levels within 12 weeks post pregnancy [23]. We focus on individuals with MUD within six months prior to conception instead of those with sporadic use, as they are at highest risk for return to use. We included those with cravings without MU within six months prior to conception as this is a criterion of active MUD. Individuals with opioid use disorder (OUD) are also included as 78 % of individuals in the primary recruiting site have co-occurring MUD and OUD [24,25].

2.2.1 Inclusion criteria

Potential participants must meet all inclusion criteria for PROMPT eligibility including.• DSM-V criteria of any severity for MUD in the 6 months prior to conception, during pregnancy or within twelve weeks postpartum [22].o Cravings, urges and dreams of use are included as symptoms of the SUD. These can occur in the absence of active MU

• No active MU within four weeks prior to enrollment based on either self-report or urine toxicology, a reliable measure of establishing abstinence in research settings [[26], [27], [28]].

• If diagnosis of active OUD (defined as DSM-V criteria of any severity in past six month with self-report or urine toxicology consistent with non-prescribed opioids) must be on stable dose of medication (methadone, buprenorphine, naltrexone) for two weeks prior to enrollment to allow for postpartum dose adjustments.oNo misuse of opioids at time of enrollment or within four weeks prior to enrollment by self-report or urine toxicology.

oPrescribed opioids for pain management for medical procedures including birth are acceptable if ≥ two weeks from enrollment.

• Intrauterine device, barrier method or permanent female sterilization (e.g. tubal ligation) for contraception during the study period

• End of pregnancy within past 12 weeks

• Residing within 100 miles of study site

• No plans to move more than 100 miles from study site within study period

• Have phone and/or able to provide collateral contact information for two individuals

• Ability to provide informed consent

• Stable on allowable psychiatric medications including selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, and mood stabilizers for four weeks prior to enrollment

2.2.2 Exclusion criteria

Potential participants may not meet any exclusion criteria including.• Major medical illness in which progesterone may be contraindicated (significant liver disease, history of thrombophlebitis, stroke, heart disease, suspected or known malignancy, deep venous thrombosis, pulmonary embolism, bleeding disorders) per principal investigator (PI) and/or medical clinician (MC) assessment [29].

• Any laboratory abnormalities within two weeks of screening and enrollment (Table 1)Table 1 Laboratory value and vital sign exclusion criteria.

Table 1Laboratory Values	Vital Signs	
• Active hepatic dysfunction defined as AST or ALT that is twice the upper limit of normal.

•Anemia defined as hemoglobin less than 8 g/dL.

•Renal impairment defined as creatinine greater than 2.0 mg/dL.

•Hypothyroidism defines as thyroid stimulating hormone greater than 5 mIU/L

	•Temperature <97 or >100.3 °F.

•Pulse <50 and >130 beats per minute.

•Systolic blood pressure of 160 or ≤80 and diastolic blood pressure of 110 or ≤50.

•Oxygen saturation <92 % on room air.

•Respiratory rate <9 or >20 breaths per minute.

	
AST = Aspartate Aminotransferase; ALT = Alanine Transaminase; g = grams; dL = deciliter; milligrams = mg; milli-international units = mIU; L = Liter.

• Abnormal vital signs at baseline visit (Table 1)

• Allergy to micronized progesterone or placebo ingredients (peanut oil, gelatin, cellulose)

• Self-reported progestin-containing oral or depot containing contraceptive intolerance.

• Does not speak English or Spanish

• Taking CYP450 3A4 inhibitors of including: clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, goldenseal [29].

• Severe depressive symptoms defined as Edinburgh Postnatal Depression Scale (EPDS) score of ≥19 or severe anxiety symptoms defined as Generalized Anxiety Disorder−7 (GAD−7) score of ≥15 at time of enrollment [[30], [31], [32], [33]].

• Active suicidality defined as expressing current thoughts of self-harm verbally to MC or study team member, Columbia Suicide Severity Rating Scale (C-SSRS) score >0, or EPDS Question #10 score of greater than 0

• Current psychosis

• History of psychiatric hospitalization for psychosis within the past six monthsoHospitalization for management of substance use disorder and its sequelae is not exclusionary

• Suicide attempt with or without hospitalization within the past six monthsoHistory of suicidal ideation or self-harm (e.g. cutting) with no plan for suicide are not exclusionary

• Current or known pending incarceration.

• Active alcohol use disorder within past six months

• Use of the following concomitant sedating medications or supplements in the two week prior to enrollment: stimulants, barbiturates, benzodiazepines, non-benzodiazepine hypnotics, orexin antagonists, first generation anti-histamine, herbal sedatives, methaqualone and analogues, skeletal muscle relaxants, opioids (other than methadone or buprenorphine), anti-psychotic medications, certain anti-depressants or other medication with significant sedative properties (Appendix C) as evaluated by the PI and/or study clinician.

• Progestin containing medications including the following contraceptives: oral hormonal, vaginal ring, patch, injectable or implant.

2.3 Recruitment and retention strategy

The primary recruitment location for this trial is an integrated multidisciplinary perinatal addiction clinic at an academic institution in Utah. The clinic is staffed with a multi-disciplinary team trained in perinatal SUD including maternal fetal medicine clinicians, mental health professionals, social workers, case managers, research coordinators (RCs), and clinical coordinators. This setting ensures access to a large potential study population and appropriate resources. Study information is also provided to partnering agencies including local outpatient treatment programs, addiction medicine specialists, local obstetrical clinicians, and residential treatment programs for pregnant and parenting individuals for further participant recruitment.

Retention is maintained using study visit reminders sent through participant's preferred format (phone, text, email), participant access to an RC study phone number, and virtual visits. Participants are also compensated $100 for baseline assessment and $50 for each study visit with biological samples. Participants can receive an additional $100 if all 12 study visits are completed, for a potential reimbursement total of $620.

2.4 Screening

To assess eligibility, RCs screen all potential pregnant and postpartum participants medical records for inclusion and exclusion criteria. If individuals express study participation interest and meet eligibility criteria, RC provide detailed study information and participants sign an informed consent. While potential participants may be screened and consented during pregnancy, no study intervention occurs until postpartum. Individuals who enroll and are immediately postpartum do not initiate the study medication until four days postpartum.

All enrollment medical eligibility criteria are reviewed by study MCs including medical history, medications, and laboratory test values. Study enrollment will not occur unless identified or suspected major medical conditions have resolved.

2.5 Randomization

After individuals are screened and consented, randomization occurs 1:1 with stratified random assignment of four block sizes in each stratum by 1) presence of OUD or 2) no OUD. Randomization occurs through a REDCap module. To ensure blinding of study team to treatment allocation, the institution investigational pharmacy triggers the randomization in REDCap, and prepares the study interventions. As this is a double-blinded trial, neither the RC, the MC nor the participant will know allocation group. Only the pharmacists preparing study medication and the study statistician are unblinded. Medications are created and packaged to look identical between treatment arms to guarantee blinding for study staff who dispense and collect unused medication at study visits.

2.5.1 Study medication preparation

The oral micronized progesterone dose of 400 mg (200 mg twice daily) and similar appearing placebo capsules are prepared by the academic institution investigation pharmacy. The placebo capsules are hand packed microcrystalline cellulose gelatin capsules. The institution investigational pharmacy monitors randomized medications by marking the study medication bottle with sequentially numbered containers. The RC provides the institution investigational pharmacy participant numbers and receives the study medication. The RC then provides the participant with study medications.

2.6 Intervention

After screening and consent, individuals are then randomized to 400 mg oral micronized progesterone daily (200 mg twice daily) or placebo. The progesterone dose and timeframe are consistent with the Yonkers et al., 2014 study [17]. After randomization, participants attend once weekly study sessions for 12 weeks. Progesterone administration does not start until at least four days postpartum due to theoretical risk of prolactin inhibition and subsequent decreased breastmilk production [34]. If participants report delayed onset of lactation, medication initiation will be postponed until breastmilk production occurs or participant is no longer breastfeeding. For participants who do not plan to breastfeed, the medication can be initiated any time after four days postpartum without further lactation monitoring.

2.7 Outcome measures

2.7.1 Feasibility

The primary feasibility outcome is measured by successful monthly study recruitment of eligible postpartum persons with MUD. Sample size is based on a power estimate for feasibility [35,36] and the number of potential participants who can be screened and consented within the study timeframe. Calculated based on the volume of patient visits of postpartum individuals with MUD at the primary recruitment site, a total goal of 40 participants will be randomized in this study to progesterone (n = 20) versus placebo (n = 20) if we screen and recruit over 24 months and 70 % are eligible and interested. There is an expected 20 % (n = 8) dropout rate based on previous studies, but our ability to maintain engagement has minimized this to 5–10 % [19].

2.7.2 Safety

Safety outcomes including side effect frequency, mental health status, lactation and medical complications, death, and new pregnancies during a three-month study follow-up are monitored. A Data Safety Monitoring Board (DSMB) is established by the study team and meets upon each quarter of enrollment to review participant summary measures to ensure participant safety. Potential side effects from micronized progesterone are listed in Table 2 and are monitored using the Generic Assessment of Side Effects (GASE) [37]. While prior studies among postpartum persons who received progesterone for substance use prevention showed no difference in depressive symptoms [[17], [18], [19]], mental health is monitored closely given potential risk of increased depression and anxiety from progesterone. Self-reported assessments for ongoing mental health monitoring include the EPDS, GAD-7, and C-SSRS. Lactation is monitored as progesterone can inhibit breastmilk production, though we expect the risk to be low [34]. To ensure adequate breastmilk production and screen for potential infant related adverse events, the Infant Sedation Assessment (ISA) [38], infant chart review, and Bristol Breastfeeding Assessment Tool (BBAT) are collected among lactating participants and breastfed infants only [39]. Participants are referred to a lactation consultant based on clinical assessment and participant's goals and preferences. Feasibility and safety outcome benchmarks are summarized in Table 3.Table 2 Potential micronized progesterone side effects.

Table 2More Common	Less Common	
•Dizziness

•Breast tenderness

•Headache

•Abdominal pain

•Fatigue

•Viral infection

•Abdominal distension

•Musculoskeletal pain

•Emotional lability

•Irritability

•Upper respiratory infection

	•Less breastmilk production

•Dry mouth

•Anxiety or depression

•Constipation

•Hypertension

•Bile duct blockage

•Skin rash

•Allergic reaction

•Acne

•Urinary tract infection

•Abnormal liver function

•Deep vein thrombosis or pulmonary embolism

	

Table 3 Feasibility and safety outcome benchmarks.

Table 3Feasibility	Benchmark	
Average monthly accrual (participants/month) (primary)	1.6/month	
Number of participants enrolled in 24 months	40	
Retention Dropout rate	<20 %	
Compliance: Number of pills taken	≥80 %	
Adherence: Study session completion	≥80 %	
Safety	Benchmark	
Side effects attributed to medication	<20 % positive	
EPDS or GAD7 score increase ≥30 %	≤5 %	
Suicidal ideation	≤5 %	
Hospitalizations	≤5 %	
Breastfeeding difficulty	≤30 %	
New pregnancy	≤5 %	
Deep vein thrombosis and/or pulmonary embolism	≤5 %	
Death	0 %	
EPDS = Edinburgh Postpartum Depression Scale; GAD 7 = Generalized Anxiety Disorder 7.

2.7.3 Preliminary estimate of efficacy

Preliminary estimate of efficacy is assessed by evaluating return to MU and time to return to use by either self-report or urine toxicology testing. Return to MU and abstinence is based on a urine toxicology test or Substance Use Calendar (SuCal), a validated self-reporting tool [40]. SuCal is based on a Timeline Follow back and is a reliable method for daily information collection on quantity and frequency of MU. The urine toxicology test is a two-step process: First, an immunoassay for the qualitative detection of substances including amphetamines, opiates, buprenorphine, methadone, oxycodone, and benzodiazepines using the Siemens Emit II urine toxicology panel (sensitivity and specificity of all substances is >95 %), however false positive results for amphetamines are frequent [41]. Therefore, a confirmatory test using mass-spectrometry is reflexed to quantify amphetamines, cannabinoids, opioids (including oxycodone, methadone, or buprenorphine), benzodiazepines, and their metabolites. If participant experiences return to use, they are offered additional resources including medication management, social work referral for behavioral health, peer support, and escalation of treatment including referral to substance use treatment partners and residential treatment programs for postpartum or parenting individuals.

2.7.4 Allopregnanolone levels and methamphetamine craving

The Stimulant Craving Questionnaire-Brief (STCQ-Brief) is used to measure methamphetamine craving and has good external and internal validity [42]. Salivary samples are collected in a tube and processed using a highly sensitive enzyme immunoassay. Allopregnanolone salivary sample collection is further specified in Appendix D. All outcomes are assessed using statistical methods in Appendix E.

2.8 Monitoring

2.8.1 Baseline visit

The baseline visit includes a full medical history, medication, and lab review by study MC (Table 4). MUD of any severity is confirmed using the DSM-V checklist. The SuCal assesses MU 28 days prior to baseline visit and urine toxicology establish no MU for at least 4 weeks.Table 4 Timeline of questionnaires and assessments.

Table 4Time point Week	Baseline	1	2	3	4	5	6	7	8	9	10	11	12	
Medical History, Medications & Lab Review	✓													
DSM V Checklist	✓													
SCQ-Brief	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	
Bristol BAF	✓													
SuCal (28 days prior to enrollment)	✓													
SuCal (7 days prior or since last visit)		✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	
Administration of study medication	✓		✓		✓		✓		✓		✓			
Pill count of returned med			✓		✓		✓		✓		✓		✓	
C-SSRS (2 weeks prior to randomization)	✓													
C-SSRS Since Last Visit		✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	
GASE Side effects		✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	
IBSA		*	*	*	*	*	*	*	*	*	*	*	*	
Breastfed Infant chart review		*	*	*	*	*	*	*	*	*	*	*	*	
EPDS	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	
GAD-7	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	
CBC, CMP, TSHA	✓													
Salivary sample	✓		✓		✓		✓		✓		✓		✓	
Urine pregnancy test	✓						✓						✓	
Urine toxicology	✓		✓		✓		✓		✓		✓		✓	
DSM V = Diagnostic and Statistical Manual V; SCQ-Brief = Stimulant Craving Questionnaire; Bristol BAF =Bristol Breastfeeding Assessment Form; SuCal = Substance Use Calendar; C-SSRS Colorado – Suicide Severity Rating Scale GASE = Generic Assessment of Side Effects; IBSA = Infant Breastfeeding and Sedation Assessment; EPDS = Edinburgh Postpartum Depression Scale, GAD 7 = Generalized Anxiety Disorder 7; CBC = Complete Blood Count; CMP = Complete Metabolic Panel; TSH = Thyroid Stimulating Hormone.

✓ = will be collected at each visit.

* = will be collected as needed for breastfed infants only.

A = if results not available 2 weeks prior to enrollment.

To ensure there are no significant laboratory abnormalities meeting exclusion criteria, laboratory values are reviewed by the MC. Complete blood count, complete metabolic panel, thyroid stimulating hormone and urine pregnancy test are reviewed. Baseline salivary allopregnanolone levels are obtained. For lactating participants, a BBAT is completed once at baseline assessing components of efficient lactation [39]. Baseline mental health assessments are assessed using the EPDS, GAD-7, and C-SSRS. The MC discusses risks and benefits of progesterone for those with moderate depression or anxiety.

After consent and enrollment, participants are instructed to take their initial randomized medication dose the evening of receiving the study medication and twice daily thereafter, in the morning and evening as close to 12 h apart with food for the next 12 weeks. Participants may use a dosing calendar to monitor compliance.

2.8.2 Follow-up visits

Study visits occur every 7 days ( ± 3 days) for 12 weeks after enrollment. If participants are unable to be seen within this targeted timeframe, then they are seen as soon as possible. Full study visits occur at weeks 2, 4, 6, 8, 10, and 12 in clinic or a research room. Phone or virtual visits occur weeks 1, 3, 5, 7,9, and 11 unless the participant prefers an in-person visit. Participant retention is facilitated with home or off-site visits in public areas or within the participant's residence.

During full study visit, RCs obtain urine and salivary samples, review of dosing calendar and returned pill counts and provide study medication. At these visits, participants are asked about MU in the last seven days or since the last study visit suing SuCal [40]. They also asked about mental health monitoring, substance use, and side effects include the GASE, SCQ-Brief, EPDS, GAD-7, and CSSRS. The ISA and infant medical record review are obtained for breastfed infants only.

2.9 Safety monitoring

2.9.1 Mental health monitoring

Mental health is monitored closely given potential increased risk of depression and anxiety from progesterone. Patients with severe depression defined as having an EPDS score of ≥ 19 or anxiety with a GAD-7 of ≥ 15 after enrollment, are evaluated by a qualified mental health professional the same day. Moderate depression or anxiety as indicated by an EPDS score of 14–19 or GAD-7 of 10–14 prompts MC or PI notification. If participants have suicidal ideation based on self-report, or EPDS Question #10 score of >0, or C-SSRS score >0, then a Quick Suicide evaluation will be implemented (Fig. 2). RCs can also contact the PI and/or MC for evaluation and triage within 24 h if they have concerns about worsening emotional well-being despite GAD-7, EPDS, C-SSRS, or GASE findings. The PI and/or MC determines appropriate triage to other mental health services, emergency evaluation, initiation, or adjustment of medications. Study medication is deferred until clinical stabilization is established and study criteria are met.Fig. 2 Quick suicide Screening.

UNI Crisis line = University of Utah Crisis line; PI = principal investigator; UNI/MCOT = University of Utah mental health Institute/Mobile Crisis Outreach teams.

Fig. 2

2.9.2 Adverse events

For further monitoring and safety, participant, and breastfed infant adverse events (AEs) are collected from when the participant initiates the study medication until 24 h after the final study medication dose (elimination half-life of progesterone 5–10 h). All AEs and serious adverse events (SAEs) are recorded. SAEs include infant or maternal death, hospital readmission, and ICU admission during the study period. AEs and SAEs are followed through resolution using chart review or phone calls. Events are reported to the local IRB, participating investigators, and the Food and Drug Administration (FDA). In the event of participant self-report of return to MU or other substance use or positive unexpected urine toxicology, RC will contact MC for assessment, medical treatment and potential referral to higher level of care. If a participant is parenting a dependent minor, the MC will assess safety and follow local mandated reporting laws. As this is a National Institutes of Health funded study, a Certificates of Confidentiality is automatically issued given collection of sensitive information, protecting the privacy of research participants by prohibiting disclosure of identifiable, sensitive research information to anyone not connected to the research except when the participant consents or in a few other specific situations (medical treatment, mandated reporting of potential child abuse) [43].

The occurrence of each AE and SAE may be compared between treatment arms using Fisher's Exact test or Pearson's chi-2 test as appropriate. Further participant management is outlined in Appendix F. Any protocol amendments are communicated to research staff, participants, the IRB, and the FDA. Data is confidential and stored in a secured password protected REDCap ® web application. Research staff will have access to the final data set. Outcomes will be shared through peer-reviewed publications.

2.10 Statistical analysis

2.10.1 Feasibility and safety

For the primary outcome of feasibility, we will number of enrolled participants as well as number enrolled monthly and 95 % confidence interval. Accrual outcomes will be summarized for the whole cohort. Retention, compliance (number of pills taken), adherence (number of study sessions completed), and safety outcomes (Table 3) will be summarized overall and by randomization arm, and compared at 12 weeks using an exact chi-square, and over time using Kaplan Meier methodology and a log rank statistic.

2.10.2 Preliminary estimate efficacy

For the outcome of preliminary estimate of efficacy, analyses will be conducted using the intent-to-treat principle with all randomized participants. We will assess the success of randomization using independent sample t-test and chi square analyses to compare demographic characteristics of the subjects in the placebo and the progesterone group. We will assume any participant lost to follow-up to have returned to use. The preliminary estimate of efficacy endpoint will be dichotomous return to use at or before 12 weeks based on either self-report or positive urine toxicology for methamphetamine. While definitive estimation and hypothesis testing are not the aim of this pilot study, the target sample sizes will allow estimation of odds ratios and 95 % confidence intervals comparing outcome rates in the treatment and control arms. We will assess the odds of return to MU, opioids, and any other substance use by treatment arm. We will assess OUD as an interacting variable in the logistic regression model. As a secondary analysis, we will compare relative risk of use at each week using a generalized linear mixed effects (GLIMMIX) regression model with a log link and a binomial distribution. A GLIMMIX model accounts for correlation within-patient over time. We will use Cox proportional hazards regression to compare treatment groups with time to first use after baseline as the dependent variable. A per-protocol analysis will include only participants who were compliant with the medication regimen.

2.10.3 Allopregnanolone levels and methamphetamine cravings

The association between longitudinally sampled allopregnanolone and continuous methamphetamine craving will be assessed in a linear mixed effects regression model. The distribution of allopregnanolone will be assessed and analyzed on a log scale if right skewed. Craving score will be the continuous outcome, and main effects will be parameterized as allopregnanolone, treatment arm, and their interaction. If the relationship of allopregnanolone and craving does not differ by treatment arm, we will also report the main effect of allopregnanolone on craving, while adjusting for randomization arm. Participants will be the random effect in a mixed-effects modeling approach. In sensitivity analysis, we will consider adjusting for breastfeeding, depression, anxiety, socioeconomic variables, tobacco, and other substance use as sample size permits. As secondary analyses, we will use this methodology to assess the association between longitudinally sampled allopregnanolone and continuous EPDS and GAD7, an anxiety screening tool (see Appendix).

3 Discussion

This innovative study targets postpartum individuals with MUD, a vulnerable population historically excluded from clinical trials [44,45]. Though studies have assessed progesterone treatment for prevention of return to cocaine and tobacco use among postpartum persons [[17], [18], [19]], no prior studies have assessed the outcomes of micronized progesterone on MU among postpartum individuals. Additionally, PROMPT evaluates the association between salivary allopregnanolone levels and methamphetamine cravings while prior studies only assessed progesterone levels and cravings [[17], [18], [19]]. Assessment of this relationship can help provide further understanding of the underlying proposed mechanism of progesterone metabolism to allopregnanolone, regulating GABA transmission enhancement to attenuate drug reward [20,21].

4 Strengths and limitations

This trial has multiple strengths. Bias and confounding are limited as this is a double-blind placebo RCT. The study team recruits potential participants primarily through a multidisciplinary perinatal substance use clinic. There are multiple patient engagement methods to ensure enrollment and retention including an RA study telephone participants can contact, home or off-site visits, visit reminders, and participant compensation to minimize dropout rates. The study uses validated self-reported measurements and reliable laboratory tests to increase internal validity.

There are also some limitations to this study. Though the study team has access to a large potential participant population, this is limited to a convenience sample in one urban tertiary care clinic likely limiting outcome generalizability. However, this is a pilot study, and if results show promise, it will expand the subsequent work to other diverse geographic locations and further strengthen generalizability. Furthermore, medication compliance may have discrepancies. To address this, a pill count of returned study medication is done during visits 2,4,6,8, and 12 to assess possible medication compliance inconsistencies.

Given the devastating consequences of return to MU among postpartum individuals [7,8,12,46], studies are needed that are tailored to this population and rooted in postpartum and addiction physiology. Micronized progesterone offers a potential novel pharmacological intervention to decrease return to MU for postpartum individuals with MUD that, if effective, can save lives.

Funding

This study was supported by the National Institutes of Health [Grant number 5R21DA053463-02 , 3R21DA053463-02S1 ]. REDCap platform is supported was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR002538 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Financial disclosure

The University of Utah receives funds to support Marcela. C. Smid from Gilead Science Inc for a study on hepatitis C treatment in pregnancy and Jada device from Alydia/Organon Inc. She serves as a consultant for Organon and Rhia Ventures. The University receives funds to support Jasmin E Charles from Gilead Science Inc for a study on hepatitis C treatment in pregnancy. She also serves as a consultant for Gilead Science Inc.

CRediT authorship contribution statement

Marcela C. Smid: Writing – review & editing, Writing – original draft, Supervision, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization, Jerry. Natasha Seliski: Writing – review & editing, Writing – original draft. Jasmin E. Charles: Writing – review & editing, Writing – original draft, Supervision, Project administration, Methodology, Investigation, Conceptualization. Stephanie Castro: Writing – review & editing, Writing – original draft, Resources, Project administration, Methodology. Grace E. Humiston: Writing – review & editing, Writing – original draft, Supervision, Project administration, Methodology, Investigation. Elysha Cash: Writing – review & editing, Writing – original draft, Project administration, Methodology, Investigation. Amanda Allshouse: Writing – review & editing, Writing – original draft, Validation, Supervision, Software, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization. Elizabeth Turner: Writing – review & editing, Writing – original draft, Supervision, Resources, Methodology. Marie Gibson: Writing – review & editing, Writing – original draft, Funding acquisition, Conceptualization. Adam J. Gordon: Writing – review & editing, Writing – original draft, Project administration, Investigation, Funding acquisition, Formal analysis, Conceptualization. Gerald T. Cochran: Writing – review & editing, Writing – original draft, Supervision, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Unrelated to this work, the University of Utah receives funds to support Marcela. C. Smid from Gilead Science Inc for a study on hepatitis C treatment in pregnancy and Jada device from Alydia/Organon Inc. She serves as a consultant for Organon and Rhia Ventures. The University receives funds to support Jasmin E Charles from Gilead Science Inc for a study on hepatitis C treatment in pregnancy. She also serves as a consultant for Gilead Science Inc.

Appendix A Supplementary data

The following are the Supplementary data to this article.Multimedia component 1

Multimedia component 1

Multimedia component 2

Multimedia component 2

Data availability

No data was used for the research described in the article.

☆ Each author has confirmed compliance with the journal's requirements for authorship.

Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.conctc.2024.101359.
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References

1 Young-Wolff K.C. Slama N.E. Sarovar V. Trends in self-reported and biochemically verified cocaine and methamphetamine use among pregnant individuals in northern California, 2011-2019 JAMA Netw. Open 5 12 2022 e2248055
2 Admon L.K. Bart G. Kozhimannil K.B. Richardson C.R. Dalton V.K. Winkelman T.N.A. Amphetamine- and opioid-affected births: incidence, outcomes, and costs, United States, 2004-2015 Am J Public Health 109 1 2019 148 154 30496001
3 Smid M.C. Allshouse A.A. McMillin G.A. Umbilical cord collection and drug testing to estimate prenatal substance exposure in Utah Obstet. Gynecol. 140 2 2022 153 162 35852263
4 Smid M.C. Allshouse A.A. Metz T.D. Co-occurring opioid and methamphetamine use disorder and severe maternal morbidity and mortality in Utah American journal of obstetrics & gynecology MFM 6 1 2024 101221
5 Bruzelius E. Martins S.S. US trends in drug overdose mortality among pregnant and postpartum persons, 2017-2020 JAMA 328 21 2022 2159 2161 36472602
6 Forray A. Merry B. Lin H. Ruger J.P. Yonkers K.A. Perinatal substance use: a prospective evaluation of abstinence and relapse Drug Alcohol Depend. 150 2015 147 155 25772437
7 Metz T.D. Rovner P. Hoffman M.C. Allshouse A.A. Beckwith K.M. Binswanger I.A. Maternal deaths from suicide and overdose in Colorado, 2004-2012 Obstet. Gynecol. 128 6 2016 1233 1240 27824771
8 Smid M.C. Maeda J. Stone N.M. Standardized criteria for review of perinatal suicides and accidental drug-related deaths Obstet. Gynecol. 136 4 2020 645 653 32925616
9 Chapman S.L. Wu L.T. Postpartum substance use and depressive symptoms: a review Women Health 53 5 2013 479 503 23879459
10 Schiff D.M. Nielsen T. Terplan M. Fatal and nonfatal overdose among pregnant and postpartum women in Massachusetts Obstet. Gynecol. 132 2 2018 466 474 29995730
11 Darlington C.K. Clark R. Jacoby S.F. Outcomes and experiences after child custody loss among mothers who use drugs: a mixed studies systematic review Drug Alcohol Depend. 251 Oct 1 2023 10094
12 Forray A. Foster D. Substance use in the perinatal period Curr Psychiatry Rep 17 11 2015 91 26386836
13 Larson E.B. Anker J.J. Gliddon L.A. Fons K.S. Carroll M.E. Effects of estrogen and progesterone on the escalation of cocaine self-administration in female rats during extended access Exp. Clin. Psychopharmacol 15 5 2007 461 471 17924780
14 Feltenstein M.W. Byrd E.A. Henderson A.R. See R.E. Attenuation of cocaine-seeking by progesterone treatment in female rats Psychoneuroendocrinology 34 3 2009 343 352 18977603
15 Sinha R. Fox H. Hong K.I. Sofuoglu M. Morgan P.T. Bergquist K.T. Sex steroid hormones, stress response, and drug craving in cocaine-dependent women: implications for relapse susceptibility Exp. Clin. Psychopharmacol 15 5 2007 445 452 17924778
16 Evans S.M. Foltin R.W. Exogenous progesterone attenuates the subjective effects of smoked cocaine in women, but not in men Neuropsychopharmacology 31 3 2006 659 674 16160708
17 Forray A. Gilstad-Hayden K. Suppies C. Bogen D. Sofuoglu M. Yonkers K.A. Progesterone for smoking relapse prevention following delivery: a pilot, randomized, double-blind study Psychoneuroendocrinology 86 2017 96 103 28926762
18 Allen S.S. Allen A.M. Lunos S. Tosun N. Progesterone and postpartum smoking relapse: a pilot double-blind placebo-controlled randomized trial Nicotine Tob. Res. 18 11 2016 2145 2153 27613934
19 Yonkers K.A. Forray A. Nich C. Progesterone reduces cocaine use in postpartum women with a cocaine use disorder: a Randomized,Double-blind study Lancet Psychiatr. 1 5 2014 360 367
20 Stephens D.N. King S.L. Lambert J.J. Belelli D. Duka T. GABA(A) receptor subtype involvement in addictive behaviour Genes Brain Behav 16 1 2017 149 184 27539865
21 Peltier M.R. Sofuoglu M. Role of exogenous progesterone in the treatment of men and women with substance use disorders: a narrative review CNS Drugs 32 5 2018 421 435 29761343
22 American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders fifth ed. 2022 Washington D.C. 10.1176/appi.books.9780890425787
23 Meltzer-Brody S. Kanes S.J. Allopregnanolone in postpartum depression: role in pathophysiology and treatment Neurobiol Stress 12 2020 100212
24 Spencer M.R. Minino A.M. Garnett M.F. Co-Involvement of opioids in drug overdose deaths involving cocaine and psychostimulants, 2011-2021 NCHS Data Brief 474 2023 1 8
25 Jarlenski M.P. Paul N.C. Krans E.E. Polysubstance use among pregnant women with opioid use disorder in the United States, 2007-2016 Obstet. Gynecol. 136 3 2020 556 564 32769641
26 Bharat C. Webb P. Wilkinson Z. Agreement between self-reported illicit drug use and biological samples: a systematic review and meta-analysis Addiction 118 9 2023 1624 1648 37005867
27 Shulman M. Choo T.H. Scodes J. Secondary analysis of agreement between negative timeline follow back report and negative urine toxicology in a large trial of individuals with opioid use disorder J Addict Med 17 5 2023 618 620 37788622
28 Shadloo B. Baheshmat S. Rostam-Abadi Y. Shakeri A. Gholami J. Rahimi-Movaghar A. Comparison of self-reported substance use with biological testing among treatment-seeking patients with opioid use disorder J. Subst. Abuse Treat. 134 2022 108555
29 Solvay Pharmaceuticals inc. Prometrium (progesterone) [package insert]. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019781s013lbl.pdf. Revised June 2009. Accessed October 15, 2023.
30 Standeven L.R. McEvoy K.O. Osborne L.M. Progesterone, reproduction, and psychiatric illness Best Pract. Res. Clin. Obstet. Gynaecol. 69 2020 108 126 32723604
31 Cox J.L. Holden J.M. Sagovsky R. Detection of postnatal depression. Development of the 10-item Edinburgh postnatal depression scale The British journal of psychiatry : J. Ment. Sci. 150 1987 782 786
32 Spitzer R.L. Kroenke K. Williams J.B. Lowe B. A brief measure for assessing generalized anxiety disorder: the GAD-7 Arch. Intern. Med. 166 10 2006 1092 1097 16717171
33 Posner K. Brown G.K. Stanley B. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults Am J Psychiatry 168 12 2011 1266 1277 22193671
34 Cho B.N. Suh Y.H. Yoon Y.D. Lee C.C. Kim K. Progesterone inhibits the estrogen-induced prolactin gene expression in the rat pituitary Mol. Cell. Endocrinol. 93 1 1993 47 52 8319833
35 Moore C.G. Carter R.E. Nietert P.J. Stewart P.W. Recommendations for planning pilot studies in clinical and translational research Clin Transl Sci 4 5 2011 332 337 22029804
36 Leon A.C. Davis L.L. Kraemer H.C. The role and interpretation of pilot studies in clinical research J. Psychiatr. Res. 45 5 2011 626 629 21035130
37 Rief W. Barsky A.J. Glombiewski J.A. Nestoriuc Y. Glaesmer H. Braehler E. Assessing general side effects in clinical trials: reference data from the general population Pharmacoepidemiol. Drug Saf. 20 4 2011 405 415 21442687
38 Winhusen T. Lofwall M. Jones H.E. Medication treatment for opioid use disorder in expectant mothers (MOMs): design considerations for a pragmatic randomized trial comparing extended-release and daily buprenorphine formulations Contemp. Clin. Trials 93 2020 106014
39 Ingram J. Johnson D. Copeland M. Churchill C. Taylor H. The development of a new breast feeding assessment tool and the relationship with breast feeding self-efficacy Midwifery 31 1 2015 132 137 25061006
40 Sobell L.C. Sobell M.B. Timeline follow-back Measuring Alcohol Consumption 1992 Springer 41 72
41 Brahm N.C. Yeager L.L. Fox M.D. Farmer K.C. Palmer T.A. Commonly prescribed medications and potential false-positive urine drug screens Am. J. Health Syst. Pharm. 67 16 2010 1344 1350 20689123
42 Sussner B.D. Smelson D.A. Rodrigues S. Kline A. Losonczy M. Ziedonis D. The validity and reliability of a brief measure of cocaine craving Drug Alcohol Depend. 83 3 2006 233 237 16384655
43 Health; NIo Certificates of confidentiality https://grants.nih.gov/policy/humansubjects/coc.htm 2024
44 Shields K.E. Lyerly A.D. Exclusion of pregnant women from industry-sponsored clinical trials Obstet. Gynecol. 122 5 2013 1077 1081 24104789
45 Hickert A. Rowley B. Doyle M. Perinatal methamphetamine use: a review of the literature Psychiatr. Ann. 51 4 2021 189 197
46 Smith L.M. Diaz S. LaGasse L.L. Developmental and behavioral consequences of prenatal methamphetamine exposure: a review of the Infant Development, Environment, and Lifestyle (IDEAL) study Neurotoxicol. Teratol. 51 2015 35 44 26212684
