Progesterone Supplementation for HIV-positive Pregnant Women on Anti-Retrovirals (ProSPAR)

In pregnancy, cART is considered optimal for maternal health and for preventing the emergence of resistance that could compromise further care. In Canada, the majority of HIV-positive pregnant women receive a PI-based cART regimen. In the past, therapy was generally deferred until after the first trimester (if not required for maternal health) to minimize any unknown risk of teratogenicity. However, as treatment is now started earlier in HIV infection and as perinatal transmission rates are lowest in those with prolonged suppression of viral load during pregnancy, women are increasingly commencing cART either before conception or earlier in pregnancy.

Multiple reports and cohort studies provided data suggesting an association between PI-based cART use and preterm birth, low birth weight, and small for gestational age (SGA) babies, although conflicting data exist.

In the general population progesterone supplementation is widely used, is well tolerated, is considered safe, and is beneficial to prevent recurrent pre-term birth and increase birth weight. The investigators experimental findings suggest that PI use during pregnancy is associated with declines in progesterone levels that correlate with fetal growth, and that progesterone supplementation can improve PI-induced fetal growth restriction. The investigators preliminary findings in HIV+ pregnant women suggest that PI-use is associated with declines in progesterone levels, which correlate with birth weight percentile. Since HIV-positive women have higher rates of pre-term delivery and low birth weight that may be magnified by the use of PIs, then progesterone supplementation could be of benefit to neonatal health in the context of HIV-positive pregnancy.

Study Overview

• Status: Unknown
• Conditions: HIV-1 Infection
• Intervention / Treatment: Drug: Prometrium

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • London, Ontario, Canada, N6A 4V2
      • St. Joseph's Hospital
    • Toronto, Ontario, Canada, M5G 1Z5
      • Mount Sinai Hospital
    • Toronto, Ontario, Canada, M5G 2N2
      • Toronto General Hospital
    • Toronto, Ontario, Canada, M5C 2T2
      • St. Michael's Hospital
    • Toronto, Ontario, Canada, M5G 1K2
      • Maple Leaf Medical Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Documented HIV-1 infection
• On (stable) or initiating a cART regimen containing either ritonavir-boosted lopinavir (LPV/r), atazanavir (ATZ/r) or darunavir (DRV/r)
• Pregnant up to 24 weeks gestational age
• Singleton pregnancy
• 18 years or older
• Ability to give informed consent

Exclusion Criteria:

• Hypersensitivity or allergy to soya or peanut (non-active ingredient supplement in Prometrium)

• Contraindications to intravaginal progesterone use including:

  • documented hypersensitivity to Prometrium
  • active or history of breast cancer,
  • active or history of arterial thromboembolitic disease (e.g. stroke, myocardial infarction, coronary heart disease)
  • active or history of venous thromboembolism (e.g. deep venous thrombosis or pulmonary embolism) or active thrombophlebitis
  • any prior neoplasia, except for skin
  • abnormal vaginal bleeding
• Known lethal fetal anomaly
• Any contraindication to continuation of pregnancy
• Inability to communicate in English
• Prior participation in this trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Prometrium; Prometrium (progesterone capsules) intervention	Drug: Prometrium; Other Names: progesterone capsules
No Intervention: No treatment; no treatment arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total enrollment / eligible population per year	Qualitative information on the reasons to decline participation will be collected and summarized. Reasons for non-enrolling questionnaire will be used.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of progesterone supplementation during pregnancy for HIV-positive women.	The number of Grade 3 or 4 AE in the ITT vs. comparator group. The number of Grade 1 or 2 AE in the ITT vs. comparator group. AE questionnaire.	40 weeks
Acceptability of progesterone supplementation during pregnancy for HIV+ women.	Assessed in the ITT group. Acceptability based on experience with medication questionnaire. Screening questionnaire (acceptability of being recruited to no treatment arm)	40 weeks
Compliance of progesterone supplementation. Assessed in the ITT group.	Number of missed doses / total prescribed doses per patient. Compliance questionnaire	40 weeks
Barriers to adherence to progesterone supplementation. Assessed in the ITT group	Reasons for missed dose questionnaire. Reasons for missed appointment questionnaire	40 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum progesterone levels at GW25-28 and GW33-36, described by treatment group.	SD and intra-patient correlation coefficient of trough serum progesterone levels will be calculated	28 weeks, 36 weeks
Urine progesterone levels at GW25-28 and GW33-36, described by treatment group	SD and intra-patient correlation coefficient will be calculated.	28 weeks, 36 weeks
Distribution of birth weight, birth weight percentile, and gestational age at birth, compared by treatment group.	ITT and on-treatment analysis	40 weeks
Relationship between progesterone levels (serum or urine) at GW25-28 or GW33-36 and birth weight, birth weight percentile, and gestation age at birth.	assessed with spearman's rank correlation	28 weeks, 36 weeks
Serum/urine progesterone levels compared between women with and without an AE/SAE.		40 weeks
Biomarker analysis	levels of sex steroids, angiogenic, vasoactive, and inflammatory factors, factors associated with placentation, placenta dysfunction, pre-term delivery and fetal growth restriction between treatment groups	40 weeks
Placenta morphology between treatment groups	Qualitative assessment performed blinded to the arm allocation and birth outcome	40 weeks
Progesterone supplementation effect on PI drug levels	trough PI drug levels in plasma collected from women in both tx groups at baseline and each study visit. changes in drug levels over time will be evaluated.	40 weeks

Collaborators and Investigators

• Sponsor: Mount Sinai Hospital, Canada
• Collaborators: CIHR Canadian HIV Trials Network
• Investigators: Principal Investigator: Sharon Walmsley, MD, Toronto General Research Institute, UHN; Principal Investigator: Kellie Murphy, MD, Mount Sinai Hospital, Canada

Publications and helpful links

General Publications

• Siou K, Walmsley SL, Murphy KE, Raboud J, Loutfy M, Yudin MH, Silverman M, Ladhani NN, Serghides L. Progesterone supplementation for HIV-positive pregnant women on protease inhibitor-based antiretroviral regimens (the ProSPAR study): a study protocol for a pilot randomized controlled trial. Pilot Feasibility Stud. 2016 Aug 12;2:49. doi: 10.1186/s40814-016-0087-6. eCollection 2016. Erratum In: Pilot Feasibility Stud. 2017 Apr 28;3:21.

Study record dates

Study Major Dates

• Study Start: August 1, 2015
• Primary Completion (Anticipated): December 1, 2016
• Study Completion (Anticipated): December 1, 2016

Study Registration Dates

• First Submitted: March 23, 2015
• First Submitted That Met QC Criteria: March 25, 2015
• First Posted (Estimate): March 26, 2015

Study Record Updates

• Last Update Posted (Estimate): July 30, 2015
• Last Update Submitted That Met QC Criteria: July 28, 2015
• Last Verified: July 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; HIV Seropositivity; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Progestins; Progesterone
• Other Study ID Numbers: CTNPT025