E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Body weight is regulated within the hypothalamus. In rare cases mutations in genes, which are embedded in the signaling cascades of the hypothalamus lead to early onset severe obesity. POMC is one important gene and encodes the hormone Melanocortin (MSH), which regulates via the MC-4 receptor energy expenditure and satiety. Moreover within the pituitary POMC encodes the hormone ACTH. In total the failure of these hormone leads to obesity and secondary adrenal insufficiency in this POMC patients. |
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E.1.1.1 | Medical condition in easily understood language |
Mutations in the gene POMC (LEPR, or PCSK1) leads to the lack of one important hormone, which is necessary to regulate body weight. For this reason the patients develop an early onset severe obesity. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Primary objectives:
• Body weight
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E.2.2 | Secondary objectives of the trial |
Secondary objectives:
• Pubertal development
• Metabolic serum parameters (insulin, liver function)
• Blood pressure
• Body-weight after a treatment duration of 2 years |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Written informed consent by the patients or the responsible relatives
• Rare genetic disease populations in adults (≥18 years):
o Homozygous or compound heterozygous (different gene mutation on both alleles) POMC, LEPR, MC4R or PCSK1 gene mutation
o Heterozygous POMC, MC4R mutations
o POMC hypermethylation (epigenetic) variant (>51.92 % POMC methylation intensity at the specific analysed POMC region)
o Bardet-Biedl Syndrome
o Alstrom’s Syndrome
• Non-adult adolescent patients (≥ 12 years of age)
o Homozygous or compound heterozygous POMC, LEPR or MC4R gene mutations
o POMC hypermethylation (epigenetic) variant (> 35.79% POMC methylation intensity for individuals younger than 30 years at the specific analysed POMC region)
o As substantial efficacy is shown in adult patients within each rare genetic disorder, then adolescent patients (greater than or equal to 12 years of age) can enter the study.
• Obesity (BMI > 30 kg/m2; + 2 BMI SDS)
• No other therapeutic option, which might cure the patient (e.g. bariatric surgery (see chapter 8))
• Negative Pregnancy test
• Highly effective contraception in women (defined as pearl index < 1), if necessary also for partners of test persons)
• No participation in other clinical trials according to AMG (2 months before and after) at the time of this trial
• Normal or minimally elevated blood pressure (measured in 24RR monitoring or similar methods) according the guidelines of the ESH (European Society of Hypertension) and Deutsche Hochdruckliga: systolic > 159 mmHg/diastolic 99 mmHg
• sufficient kidney and liver function (Creatinine, ALT, AST)
o normal values Alanin-Aminotransferase (ALT) (female): < 31 U/l
o normal values Alanin-Aminotransferase (ALT) (male): < 41 U/l
o normal values Aspartat-Aminotransferase (AST) (female > 17 years): < 35 U/l; (female < 17 years): 16-46 U/l
o normal values Aspartat-Aminotransferase (AST) (male > 17 years): < 50 U/l; (male < 17 years): 16-46 U/l
o normal values Bilirubine (male and female) up to 1,2 mg/dl
o normal values Creatinine (female > 15 years): 0,51-0,95 mg/dl) ; (female < 15 years): 0,46-0,77 mg/dl
o normal values Creatinine (male > 15 years): 0,67 – 1,17 mg/dl) ; (male < 15 years): 0,46-0,77 mg/dl |
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E.4 | Principal exclusion criteria |
• Pregnancy or Breastfeeding
• All contraindications against study medication (including auxiliary substances)
• Interactions with study medication
• Participation of the patient in a clincial study within the last 2 months
• Intolerance against albumin
• Concomitant diseases, impaired organ functions, except for known, concurrent GI disorders or other clinical findings expected in PCSK1 or LEPR or MC4R gene disorders
• Renal insufficiency (Creatinine > 0.95 mg/dl (female), > 1.17 mg/dl (male))
• Impaired liver function (Bilirubine > 1.2 mg/dl)
• history of Neurological / psychiatric diseases
• history of HIV Infection
• history of Active Hepatitis B or C
• Melanoma or Melanoma occurrence in the family history
• Non-compliance
• Subjects who are legally detained in an official institution
• HIV Infection
• Active Hepatitis B or C
• Melanoma or Melanoma occurrence in the family history
• Non-compliance
• Subjects who are legally detained in an official institution
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E.5 End points |
E.5.1 | Primary end point(s) |
• Body weight course before and with RM-493 Treatment
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Body weight will be measured weekly throughout the study. The primary endpoint will be the body weight before and after the treatment period with RM-493. |
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E.5.2 | Secondary end point(s) |
•• Pubertal development with RM-493 treatment
• Changes of metabolic parameters (insulin, liver / kidney function)
• Blood pressure
• Body composition/Energy expenditure
• Global Hunger Score (10 point scale)
• Amendment: weight loss after treatment continuation of 2 years.
• Changes of skin and nevi color
• Psychological development of each patient during treatment
period
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- the pubertal development will be examined just before and after the treatment period with RM-493 by a clinical examination and by performing a LHRH test.
- before and after the treatment period there will be a blood collection in which metabolic parameters will be analyzed.
- Blood pressure will be analyzed over 24h before and after the treatment period. Moreover, after each dosage escalation the blood pressure will be monitored carefully in the clinic for 12 hours following the new dose. Finally, patients will have blood pressure checked 3 times per day at home.
the secondary endpoints were determined during the study visit every 6 months alternating with the 3-month visit; |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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LVLS
The trial will end after the last treatment period with RM-493 (max. 90 days) of the last of 2 patients.
There will be a follow-up period until December 2020, in which the responsible doctor will be contacted once a year. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |