Confidential TITLE PAGE SPONSOR Ferring AB Box 30047 S - 200 61 Malmo Sweden STUDY DRUG: Triptorelin (Decapeptyl@CR) CLINICAL STUDY REPORT Retrospective Study of Triptorelin CR in Central Precocious Puberty ,~ 1 INVESTIGATOR: Dr Rivka Kauli, M.D. Associate Professor of Pediatrics Institute of Pediatric and Adolescent Endocrinology the Children’s Medical Center of Israel Beilinson Campus, Sackler School of Medicine Tel Aviv University Israel DATES: First injection of triptorelin CR: 20 Oct. 1985 Last patient observation: 21 Oct. 1992 Report: 18 Mar. 1994 SIGNATURES: I, the undersigned, hereby declare that the work presented in this report was performed according to the procedures described herein and that this report provides a correct and faithful record of the results obtained. I 0 Rivka Kauli, M.D. Report prepared by: Investigator a3 h~t193Y Date Pontus Regnell, M.D. e Medical ‘adviser, Ferring 18” /9?4 . Date Signatufe
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Confidential
TITLE PAGE
SPONSOR Ferring AB Box 30047 S - 200 61 Malmo Sweden
STUDY DRUG: Triptorelin (Decapeptyl@ CR)
CLINICAL STUDY REPORT
Retrospective Study of Triptorelin CR in Central Precocious Puberty ,~ 1
INVESTIGATOR: Dr Rivka Kauli, M.D. Associate Professor of Pediatrics Institute of Pediatric and Adolescent Endocrinology the Children’s Medical Center of Israel Beilinson Campus, Sackler School of Medicine Tel Aviv University Israel
DATES: First injection of triptorelin CR: 20 Oct. 1985 Last patient observation: 21 Oct. 1992 Report: 18 Mar. 1994
SIGNATURES:
I, the undersigned, hereby declare that the work presented in this report was performed according to the procedures described herein and that this report provides a correct and faithful record of the results obtained.
I 0
Rivka Kauli, M.D.
Report prepared by:
Investigator a 3 h~t193Y Date
Pontus Regnell, M.D. e
Medical ‘adviser, Ferring 18” /9?4 . Date Signatufe
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STUDY SYNOPSIS
This retrospective study of triptorelin CR (TCR) in central precocious puberty was performed by:
Dr Rivka Kauli, M.D. Associate Professor of Pediatrics Institute of Pediatric and Adolescent Endocrinology the Children's Medical Center of Israel Beilinson Campus, Petah Tiqva Israel
The objective was to assess the long-term efficacy of TCR therapy against a central precocious puberty.
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The study focused on clinical results, such as pubertal development, and bone maturation, because these parameters correlate well with oferall efficacy and adult height (Kauli et al. 1992, Cook et al. 1992). Height, weight and hormonal results during therapy were also registered.
The 30 patients who had the longest therapy with TCR at the Institute of Pediatric and Adolescent Endocrinology were included. TCR was injected about every 4 weeks. The dose depended on body weight based on the following dose recommendation table:
Body Weight TCR Dose h mg every 4 weeks
1.25 f up to 20 20 to 30 - 35 1.875 over 30 - 35 3.75
The twenty-four patients who completed TCR therapy received a lower dose than that listed in the table above during the last few months of therapy to allow a smoother transition into puberty.
To counteract any initial stimulation by triptorelin, the patients started 75-1 00 pg/kg/day of cyproterone acetate two weeks before the first triptorelin injection and then gradually discontinued cyproterone acetate after about a month of triptorelin therapy.
Breast development, expressed in Tanner stages, stopped or even regressed in the girls. Before TCR therapy, median breast development in Tanner stages was 3. During the first year, it decreased in 13 patients and was constant in the other 15 girls. During the first three years, Tanner breast
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stage decreased in 17 patients and was constant in the other I O patients. Pubic and axillary hair development increased slowly during therapy since adrenarche is not affected by it. On the other hand the signs of gonadarche, i. e. breast development and vulvar development, decelerated or regressed, thus expressing the sustained suppression of gonadotropin secretion and confirming that puberty was under sustained control. Other signs of puberty confirm the efficacy. For example, 96 % of the girls had firm breasts before therapy, but all girls had soft breasts during therapy, showing that TCR reduced estradiol stimulation.
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Bone age was accelerated prior to therapy; thus the ratio of bone age to chronological age on average was 1.37 before therapy. TCR normalised this ratio; A bone age / A chronological age was about 0.5 during therapy.
Serum gonadotropins and sex steroids were suppressed during therapy. Thus, the girls' peak response of luteinizing hormone (LH) to a standard gonadotropin-releasing hormone (GnRH) test decreased from (mean k SD) 5.75 k 5.62 before therapy to 1 :20 k 0.57 at 1 year and to 0.68 k 0.35 at 3 years. This effect lasted during the whole study.
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In conclusion, TCR decelerated or even reversed clinical signs of precocious puberty, such as breast development and genital development. TCR normalised the ratio of bone age to chronological age, indicating that the therapy normalises predicted adult height. Sex hormone concentrations in blood samples were abnormally high before therapy, but in almost all cases normal during therapy. The results in this study, which are similar to European published results, indicate that TCR is efficacious in therapy lasting for several years.
