PRE-GAiN Bone Health Pilot Study (PRE-GAiN)

PRE-GAIN Bone Health Pilot Study - Physiologic Replacement of EstroGen for Adolescent Females With AnorexIa Nervosa for Bone Health Pilot Study

This study will assess the affects of an estradiol hemihydrate transdermal system on bone health in 24 adolescent females aged 12-19 years old with anorexia nervosa. Participants in this study will be randomized 1:1 into 2 groups. One group will receive treatment with a transdermal estrogen patch and the other group will not.

Study Overview

• Status: Recruiting
• Conditions: Anorexia Nervosa
• Intervention / Treatment: Drug: Estradiol Hemihydrate Transdermal System

Detailed Description

Currently, no therapy exists to improve bone health in females with anorexia nervosa (AN) other than improving body mass. Transdermal estrogen is being investigated as to whether it has benefit to bone health parameters.

While numerous studies have sought to orally replace estrogen in adolescents and women with AN, the replacement therapy suppresses IGF-1, and as a result oral estrogen studies have demonstrated no bone health benefit in AN. However, transdermal physiologic estrogen, due to no first-pass metabolism in the liver, is not IGF-1 suppressive. IGF-1 is known to be hormone that directly affects bone formation and is considered to be osteoanabolic (helps increase bone mass).

• Study Type: Interventional
• Enrollment (Anticipated): 24
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Simona Meier; Phone Number: 306-978-8302; Email: simona.meier@usask.ca

Study Locations

• Canada
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7N 0W8
      • Recruiting
      • Royal University Hospital
      • Contact: Munier Nour; Phone Number: (306) 655-2048; Email: munier.nour@usask.ca
      • Principal Investigator: Munier Nour

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 19 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Female
• Age 12 - 19 years old

• Meet DSM-5 criteria for Anorexia Nervosa

  o Criteria includes: persistent restriction of energy intake leading to significantly low body weight; either an intense fear of gaining weight or persistent behavior that interferes with weight gain; and a disturbance in the way one's body weight or shape is experienced

• Amenorrhea for at least three months

  • Amenorrhea is a required inclusion criteria as participants with intact menstruation do not meet justification for estrogen replacement (as they are not estrogen deficient)
  • Participants will have been seen and assessed by anorexia clinic physician prior to enrollment to exclude and treat other causes of amenorrhea
• Agree to use a highly effective contraceptive method for the duration of study therapy.

Exclusion Criteria:

• Uncontrolled or chronic medical conditions that may influence bone health (i.e. hyperthyroidism, diabetes mellitus, or celiac disease)
• Use of supraphysiologic corticosteroids for greater than three months
• Pregnancy or attempting pregnancy
• Cigarette smoker
• Known history of a blood clotting disorder (i.e. Factor V Leiden, Protein C Deficiency, etc.)
• Known predisposition to estrogen-related cancers, such as breast or ovarian cancer (e.g. BRCA1)
• Hypersensitivity to this drug or to any ingredient in the formulation or component of the container
• Liver dysfunction or disease as long as liver function tests have failed to return to normal
• Known or suspected estrogen-dependent malignant neoplasia (e.g. endometrial cancer)
• Endometrial hyperplasia
• Known, suspected, or past history of breast cancer
• Undiagnosed abnormal genital bleeding
• Known or suspected pregnancy or lactation
• Active or past history of arterial thromboembolic disease (e.g. stroke, myocardial infarction, coronary heart disease)
• Active or past history of confirmed venous thromboembolism (such as deep vein thrombosis or pulmonary embolism) or active thrombophlebitis
• A high risk of venous or arterial thrombosis, including known thrombophilic disorders
• Partial or complete loss of vision due to ophthalmic vascular disease
• Presence or history of liver tumours (benign or malignant)
• Ongoing use of estrogen containing contraception (oral birth control pill, vaginal ring, patches, depo injections)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment; Participants randomized to the treatment arm will be divided by maturational status: Participants who have had their first period or have a bone age greater than or equal to 14 years will receive PrClimara® 25 (estradiol hemihydrate transdermal system - 25 mcg/day) as a weekly patch, for 24 months.o These participants will also receive progesterone (Provera 10 mg tablet) orally every 4 weeks, for 7 days during the second half of the planned menstrual cycle, in order to induce a menstrual period.; Participants who have not yet had their first period and have a bone age below 14 years will receive an increasing dose of estrogen. These participants will be initiated on graduated dose of transdermal 17-β estradiol patches:3.1 mcg/day (1/8 patch) for first six-months,6.2 mcg/day (1/4 patch) for second six-months,12.5 mcg/day (1/2 patch) for third six-months, and25 mcg/day (full patch) for final six-months.	Drug: Estradiol Hemihydrate Transdermal System; Participants who have had their first period or have a bone age greater than or equal to 14 years will receive PrClimara® 25 (estradiol hemihydrate transdermal system - 25 mcg/day) as a weekly patch, for 24 months. Participants who have not yet had their first period and have a bone age below 14 years will receive an increasing dose of estrogen. These participants will be initiated on graduated dose of transdermal 17-β estradiol patches: 3.1 mcg/day (1/8 patch) for first six-months, 6.2 mcg/day (1/4 patch) for second six-months, 12.5 mcg/day (1/2 patch) for third six-months and 25 mcg/day (full patch) for final six-months.; Other Names: PrClimara® 25
No Intervention: No Treatment; The participants in this group will not receive the estrogen patch nor the oral progesterone.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cortical Wall Thickness	Cortical wall thickness as measured by high resolution peripheral quantitative computed tomography (HR-pQCT).	Change from Baseline to Month 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Areal Bone Content	Areal bone content as measured by high resolution peripheral quantitative computed tomography (HR-pQCT).	Change from Baseline to Month 24
Bone Micro-architectural Parameters	Bone micro-architectural parameters as measured by high resolution peripheral quantitative computed tomography (HR-pQCT).	Change from Baseline to Month 24
Volumetric Bone Density	Volumetric bone density as measured by high resolution peripheral quantitative computed tomography (HR-pQCT).	Change from Baseline to Month 24
Bone Strength Estimates	Bone strength estimates as measured by high resolution peripheral quantitative computed tomography (HR-pQCT).	Change from Baseline to Month 24
Vertebral Fracture Rates	Vertebral fracture rates as measured by lateral spine x-ray	Change from Baseline to Month 24

Collaborators and Investigators

• Sponsor: University of Saskatchewan
• Collaborators: Jim Pattison Children's Hospital Foundation
• Investigators: Principal Investigator: Munier Nour, Faculty

Study record dates

Study Major Dates

• Study Start (Actual): January 21, 2020
• Primary Completion (Anticipated): December 31, 2022
• Study Completion (Anticipated): December 31, 2022

Study Registration Dates

• First Submitted: July 12, 2019
• First Submitted That Met QC Criteria: July 12, 2019
• First Posted (Actual): July 16, 2019

Study Record Updates

• Last Update Posted (Actual): May 17, 2021
• Last Update Submitted That Met QC Criteria: May 13, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: estrogen; IGF-1; anorexia; bone health; bone accrual
• Additional Relevant MeSH Terms: Mental Disorders; Signs and Symptoms, Digestive; Feeding and Eating Disorders; Anorexia; Anorexia Nervosa; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptive Agents, Female; Estradiol; Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Polyestradiol phosphate
• Other Study ID Numbers: PRE-GAiN-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No