| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hypothalamic obesity (HO) is characterized by significant weight gain that can occur after extensive suprasellar operations or other lesions to the hypothalamus |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10013367 |
| E.1.2 | Term | Disorders of the pituitary gland and its hypothalamic control |
| E.1.2 | System Organ Class | 100000004860 |
|
| 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 |
| The primary objectives of the study is to examine the efficacy of Tesomet on body weight |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are:
• To examine the proportion of subjects with at least 5% body weight loss from baseline
• To examine change in body weight
• To examine change from baseline in waist circumference
• To examine change from baseline in BMI
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject and, if applicable, their parent or legal guardian must be willing to sign and receive a copy of the informed consent form (ICF) after the nature and risk of study participation have been fully explained
Note: Subjects under the age of consent should provide written assent with a written consent provided by a guardian, as per local requirements.
2. Female and male subjects >= 16 years of age at the time of informed consent
3. Female subjects of non-childbearing potential (WONCBP) defined as: prior menarche, postmenopausal (no menses for 12 months without
an alternative medical cause and FSH > 30mIU/ml at screening), permanently sterile (permanent sterilization methods include hysterectomy, or bilateral salpingectomy and bilateral oophorectomy ≥6 months prior to the first dose of study drug);
4. Female subjects who have a confirmed diagnosis (prior to screening) of hypogonadotropic hypogonadism as determined and documented by low estradiol, low FSH, low LH, and amenorrhea. If premenopausal the diagnosis should be confirmed at a time point prior to initiating treatment with estradiol/gestagen. Postmenopausal women with hypogonadotropic hypogonadism must have amenorrhea and low FSH and low LH for 1 year.
5. Diagnosis of HO secondary to damage to the hypothalamus
Note: Diagnosis of HO secondary to damage to the hypothalamus includes suprasellar tumor, suprasellar surgery, traumatic injury, or irradiation (focal or local), confirmed by medical history documenting temporal relationship between damage and increase in body weight and substantiated as applicable by imaging visualizing tumor, description of surgical procedure, description of radiation therapy, and need for hormone replacement therapy
6. At least 6 months since completion of therapy (chemotherapy, surgery, or radiation with resulting injury to the hypothalamus and/or the pituitary) with stable disease and lack of recurrence
7. Body mass index (BMI; body weight [kg] / height [m2]) of 30.0 to 60.0 kg/m2, inclusive, at Screening
8. Documented stable body weight (gain/loss <10%) for at least 90 days prior to Screening
9. Stable and well-managed pituitary replacement (eg, glucocorticoid, thyroid hormone, estrogen/progestin or testosterone, desmopressin, or growth hormone) for >2 months prior to Screening, as judged by the Investigator
10. Type 2 diabetes mellitus (T2DM) is allowed, provided that all of the following criteria are met:
a. Hemoglobin A1c (HbA1c) <8.5% at Screening; and
b. Subjects being treated for T2DM must have been on a stable dose of anti-diabetic medication for 90 days prior to Screening
11. Female subjects of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline
12. Female subjects of childbearing potential and male subjects must be willing to use a highly effective form of birth control from Screening until 90 days after their last dose of study drug;
13. Male subjects must agree not to donate sperm from the first dose of study drug until 90 days after the last dose of study drug |
|
| E.4 | Principal exclusion criteria |
1.Genotypic cytochrome CYP2D6-poor metabolizers and CYP2D6 ultra-rapid metabolizers, as confirmed by central laboratory at Screening
2.Use of any prohibited medication
3.Sitting BP that meets the following criteria after 5 minutes of rest at Screening:
a.Subjects with systolic BP >145 mmHg or <100 mmHg; or b.Subjects with diastolic BP >95 mmHg or <70 mmHg;
4.HR >95 bpm or <50 bpm at Screening and Baseline;
5.Corrected QT interval using Fridericia’s formula >450 msec for males and >470 msec for females at Screening based on central review
6.Hypersensitivity or contraindication to tesofensine or metoprolol
7.Type 1 diabetes mellitus
8.History of clinically significant cardiac disorders as determined by the Investigator
9.Medical history of stroke or transient ischemic attack
10.Subjects who experienced any of the following clinical symptoms or conditions within 90 days prior to Screening, as described by the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) and clinical judgment supported by the Brief Psychiatric Rating Scale (BPRS) administered centrally:
a.Delusions; b.Hallucinations; c.Major depressive disorder; d.Hypomania; or e.Suicidality;
11.Subjects who answer “yes” to the self-mutilation/self-injury question in the Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening and/or Baseline
12.Physical impairment which, in the Investigator’s opinion, will interfere significantly with study compliance
13.History of bulimia or anorexia nervosa
14.Uncontrolled endocrine disorders
15.Underlying liver impairment as evidenced by abnormal liver function test results at Screening, including alanine aminotransferase or aspartate aminotransferase abnormalities >3 x the upper limit of normal (ULN), or total bilirubin >1.5 x ULN (except in cases of diagnosed Gilbert’s Syndrome)
16.Underlying kidney impairment, defined as estimated glomerular filtration rate <= 60 mL/min/1.73 m2 (using the Schwartz equation), as determined by Screening laboratory assessments performed by the central laboratory
17.Subject has a rare hereditary problem of fructose intolerance, glucose galactose malabsorption, or sucrase-isomaltase insufficiency;
18.Subject without sufficient comprehension, communication ability, and cooperation to enable compliance with the study procedures and assessments
19.Subject who, in the Investigator’s judgment, is actively suicidal and therefore deemed to be at significant risk for suicide, or:
a. Subjects who answer "yes" to Question 4 of the C-SSRS on the "Suicidal Ideation" portion and the ideation occurred within 6 months prior to screening; or
b. Subjects who answer "yes" to Question 5 of the C-SSRS on the "Suicidal Ideation" portion and the ideation occurred within 6 months prior to screening; or
c. Subjects who answer "yes" to any of the suicide-related behaviors on the "Suicidal Behavior" portion of and the behavior occurred within 2 years prior to Screening
20.Subjects with a history of substance abuse, including cannabinoids and/or alcohol use disorders, as per DSM-5, or a positive urine drug test (including amphetamines, cocaine, opiates, phencyclidine, tetrahydrocannabinol, barbiturates, and benzodiazepines) at Screening
21.Participation in another interventional study (eg, of a drug, over-the-counter product, device, weight loss program, therapy) within 90 days prior to Screening or any prior participation in a tesofensine or Tesomet clinical study)
22.Subjects who have a co-existing medical condition or recent systemic infection that, in the opinion of the Investigator, could impact the safety of the subject. Each case will be evaluated individually with the Medical Monitor
23.Any subject who has had a confirmed COVID-19 infection within 90 days of screening
24.Subject received COVID-19 vaccine less than 2 weeks before baseline or subject is scheduled for a COVID-19 vaccination that will take place during their participation in the study except for booster vaccinations
25.Contact with an individual with COVID-19 infection within 14 days prior to screening, or between screening and the baseline visit
26.Subjects who have allergy to bovine-derived products, or are unable to ingest bovine-derived products due to dietary or cultural reasons
27.Subject has new onset eye pain (within 6 months prior to baseline) that is clinically unresolved, unstable and has not been medically evaluated prior to Screening
28. Subject has unstable or worsening vision within 6 months prior to baseline (one or both eyes), photophobia, or diplopia and has not been medically evaluated prior to Screening
29. History of asthma with an acute asthma exacerbation within the last 2 years (adult or adolescent asthma subjects may be considered if they are stable - defined as having normal lung function tests including peak flow, without acute asthma exacerbation within the last 2 years) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint of this study is the change in body weight (%) from Baseline to Week 36.
Safety endpoints for the double-blind period include the following:
• The incidence of TEAEs of special interest, including specified cardiovascular events, or specified psychiatric events;
• The incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs);
• The incidence of MACE;
• Laboratory evaluation (chemistry and hematology) results at Baseline and at all site visits;
• Vital sign measurements at Baseline and at Weeks 8, 16, 24, and 36;
• ECG assessments at Baseline and at Weeks 8, 16, 24, and 36;
• Holter monitoring at Screening and at Weeks 12 and 36;
• Physical examination findings at Baseline and at Weeks 8, 16, 24, and 36;
• C-SSRS administered by a trained rater at Baseline and at all visits; and
• Patient Health Questionnaire-9 (PHQ-9) self administered by the subject at Baseline and at all visits. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| from Baseline to Week 36. |
|
| E.5.2 | Secondary end point(s) |
• Proportion of subjects with at least 5% body weight loss at Week 36;
• Change in body weight (kg) from Baseline to Week 36;
• Change in waist circumference (cm) from Baseline to Week 36; and
• Change in BMI from Baseline to Week 36.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 23 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Israel |
| United States |
| Belgium |
| Denmark |
| France |
| Germany |
| Italy |
| Spain |
| Sweden |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 17 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 17 |
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