| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hypercortisolism Related to a Benign Adrenal Tumor |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hypercortisolism Related to a Benign Adrenal Tumor |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 22.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020611 |
| E.1.2 | Term | Hypercortisolism |
| E.1.2 | System Organ Class | 100000004860 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of this study is:
• to estimate SPI-62’s effect on clinical features of hypercortisolism related to a benign adrenal tumor including diabetes/impaired glucose tolerance, hyperlipidemia, hypertension, and osteopenia;
|
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are:
• to evaluate the safety of SPI-62 in patients with hypercortisolism related to a benign adrenal tumor, including changes on HPA and HPG axis biomarkers and associated AEs; and
• to assess the pharmacological effect of SPI-62 on hepatocellular cortisol/cortisone equilibrium in patients with hypercortisolism related to a benign adrenal tumor. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
The following are the main inclusion criteria:
• Adults able to provide informed consent.
• Documented characteristically benign adrenal nodule(s), either unilateral or bilateral, with a maximum individual diameter ≤ 4 cm, homogenous texture, and non-contrast computerized tomography ≤ 20 HU attenuation or proven to be non-malignant. Subjects with adenoma attenuation between 11 to 20 HU, inclusive, must have had adequate evaluation to exclude pheochromocytoma prior to performing the ONDST.
• Diagnosis of type 2 diabetes mellitus (excluding newly diagnosed subjects with less than 6 weeks of standard of care therapy and poorly controlled subjects), prediabetes or impaired glucose tolerance, either untreated or on stable standard of care treatment, based on at least one of:
o HbA1c ≥ 5.7% but not > 9.5%
o 2-hour glucose level ≥ 7.8 mmol (140 mg/dL) on a 75 g OGTT
• At least one additional documented cortisol-related morbidities, either untreated or on stable standard of care treatment:
o hypercholesterolemia with total cholesterol > 3.9 mM (150 mg/dL);
o hypertriglyceridemia with triglycerides > 2.3 mM (200 mg/dL);
o osteopenia with bone densitometry Z-score < -2.0 or T-score < -1.0;
o history or evidence of minimally traumatic or osteoporotic fracture; or
o hypertension with resting supine blood pressure > 130 but < 180 mmHg systolic or > 85 but < 120 mmHg diastolic.
• Poorly suppressible hypercortisolemia:
o Morning serum cortisol > 50 nM (1.8 mcg/dL) after a 1 mg ONDST.
o Subjects who are incompletely suppressed, but with dexamethasone < 3.3 nmol/L (130 ng/dL) will undergo a high-dose (8 mg) ONDST.
o Subjects who take estrogen-containing medicines will be evaluated based on free cortisol ≥ 2.2 nM (80 ng/dL).
o Subjects with morning serum cortisol > 138 nM (5.0 mcg/dL) after ONDST, must have the Investigator’s clinical classification as having either a diagnosis of ACS or aCs. |
|
| E.4 | Principal exclusion criteria |
The following are the main exclusion criteria:
• Diagnosis of ACTH-dependent Cushing's syndrome, pheochromocytoma, aldosterinoma, adrenocortical carcinoma, or congenital adrenal hyperplasia, or other malignancy associated hypercortisolism including history of adrenal carcinoma.
• History of adrenalectomy or planned adrenalectomy within 4 months after randomization.
• Exogenous hypercortisolism.
• Uncontrolled, clinically significant hypo- or hyperthyroidism (abnormal TSH values are acceptable as long as the free T4 values are within the normal range).
• History of idiopathic thrombocytopenia.
• Moderately impaired renal function (estimated glomerular filtration rate < 60 mL/min/1.73m2).
• History of cancer (other than non-melanoma skin, thyroid, or early-stage prostate cancer) within 3 years.
• Any major surgery, or significant post-operative sequelae, within 1 month prior to informed consent or planned during the trial.
• Pregnant or lactating.
• Positive test for SARS-CoV-2 active, transmissible infection within 4 weeks, or hospitalization for SARS-CoV-2 within 6 months, prior to randomization.
• Any other current or prior medical condition expected to interfere with the conduct of the trial or the evaluation of its results.
• Participation in any clinical trial within 3 months prior to the first dose of study drug, or longer depending on half-life of the investigational therapy.
• Diagnosis or biochemical evidence of aldosterinoma (unless co-secreting with cortisol and non-hypertensive or otherwise ineligible for, or unwilling to receive adrenalectomy).
• Evidence of inadequately treated hepatitis B (HBsAg positive) or C (hepatitis C antibody positive unless viral load adequately suppressed). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary endpoint is:
Efficacy:
1. Glycemic control
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Efficacy:
1.change from baseline at Week 12;
|
|
| E.5.2 | Secondary end point(s) |
Efficacy:
1. Hyperlipidemia
2. Hypertension
3. Osteopenia
Safety:
• AEs.
• Clinical laboratory evaluations
• 12-lead ECGs.
• Vital sign measurements
Pharmacologic:
• Effect of SPI-62 on hepatocellular cortisol and cortisone
Pharmacokinetic:
• Amounts of SPI-62 and its metabolite AS2570469 excreted in urine (over 24 hours) and remaining in blood will be reported. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy:
1. change from baseline at Week 12;
2. change from baseline at Week 12;
3. change from baseline at Week 12;
Safety:
Throughout the study
Pharmacologic:
• change from baseline at Week 12;
Pharmacokinetic:
• Throughout the study |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 |
| United States |
| France |
| Bulgaria |
| Romania |
| Germany |
| Italy |
|
| 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
|
| The end of the study is defined as the date of the last visit of the last subject in the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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