To assess the efficacy and safety of LCI699 in CD patients
ID
Source
Brief title
Condition
- Hypothalamus and pituitary gland disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Proportion of patients with mUFC <= 1 ULN at week 24, and the dose of LCI699 is
not increased above the level establised at the end of period 1
Secondary outcome
Proportion of patients with mUFC <= 1 ULN at week 24, and the dose of LCI699 is
increased above the level establised at the end of period 1
Background summary
For patients with Cushing*s disease (CD), surgical removal of the pituitary
adenoma is the first line therapy. Pituitary irradiation is another treatment
option, for patients who are not surgical candidates or have persistent or
recurrent hypercortisolism following primary pituitary surgery. However, the
response to pituitary irradiation is slow and can cause long-term complication
(hypopituitarism, secondary malignant tumors and possible increased risk of
death from cerebrovascular disease post-radiation).
Medical therapy is an attractive option for patients with CD who have
persistent of recurrent hypercortisolism after prior surgery, and for patients
with de novo CD who are not candidates for pituitary surgery or refuse to
undergo surgery. Pasireotide (Signifor), a second generation somatostatin
analoque, is the only drug currently approved in EU for the treatment of CD.
Several other drugs, like ketoconazole and metyrapone have been used off-label
for the treatment of CD. The off-label use is based on limited data and not
prospectively studied in randomized multi-center trials. Bilaterale
adrenalectomy is deferred until all other options have been exhausted. A
consequence of bilateral adrenalectomy is immediate and permanent primary
adrenal insufficiency, which requires life-long glucocorticoid and
mineralocorticoid replacement therapy and monitoring.
Therefore, a safe and effective targeted medical therapy is highly desirable in
this patient population. There is an unmet medical need for the treatment of
CD as medical treatment options are limited. Recent trials have showed that
LCI699 shows promising results in fulfilling this unmet medical need.
Study objective
To assess the efficacy and safety of LCI699 in CD patients
Study design
This is a global, multicenter, randomized , dubbel-blind fase III study.
After a screenings period of 35 days, patients who meet all eligible criteria
will start with period 1 (week 1-12) this is the individual dose titration
period. In period 2 (week 13-24) the efficacy and safety of LCI699 at the
therapeutic dose determined in period 1 will be assessed. The patients who are
considered complete responders at week 24 will be eligible for randomization.
The other patients will be followed for long-term safety. In period 3 (26-34)
the complete responders will enter the 8 week double-blind, placebo-controlled
randomized withdrawal period. In period 4 (week 35-48) all patients will
receive open-label LCI699 treatment, the dose may remain unchanged, increased,
decreased or withheld, depending on the mUFC level.
At the end of the 48 week treatment periode, the patients have the choice to
discontinue LCI699 or to enter the extension period. The extension period will
last one year.
Intervention
Treatment with LCI699
Study burden and risks
Toxicity of LCI699
Radiation exposure, DXA scan
Frequent visits and blood sampling
An overiew of all procedures during the visits are given in appendix C of the
patient information
The side effects can be found in appendix D of the patient information
it is not certain that participation in the study benefits directly, the data
can be useful for future patients.
The burden on the patients is as expected for a phase III trial
Haaksbergweg 16
Amsterdam 1101 BX
NL
Haaksbergweg 16
Amsterdam 1101 BX
NL
Listed location countries
Age
Inclusion criteria
1. Adult patients with confirmed persistent of recurrent Cushings disease
2. Patients with history of pituary surgery must be at least 30 days
post-surgery
3. Patients that received glucocorticoid replacement therapy post-operatively
must have discontinued such therapy for at least one week prior screening
4. Patients with de de novo Cushing's disease can be included only if they are
not considered candidates for surgery (e.g. poor surgical candidates,
surgically unapproachable tumors, patients who refuse to have surgical
treatment, or surgical treatment is not available)
5. Patients with a history of pituitary irradiation can be included, provided
that at least 3 years have elapsed from the tie of radiation to the time of
enrollementinto this study.
6. Patients are permitted to washout current drug therapy to meet these entry
criteria if they have a known diagnosis of Cushing's disease.
Exclusion criteria
1. Use of other investigational drugs at time of enrollment, or within 30 days
of time of enrollment
2. History hypertensitivity to LCI699 or other drugs of similar chemical classes
3. History of malignancy of any organ systems, treated or untreated, within the
past 5 years, regardless of whether there is evidence of local recurrence or
metastases.
4. Patients with risk factors for QTc prolongation or Torsade de pointes,
including: patients with baseline QTcF > 470 ms, personal of familiy history of
long QT syndrome, or concomitant medications known to prolong the QT interval,
hypokalemia, hypocalcaemia or hypomagnesemia
5. Pregnant or nursing women
6. Women with child-bearing potential, unless tehy use higly effective
contraception
7. Fertile males, unless they use a condom during intercource.
8. Patients with the compression of the optic chiasm, in order to exclude
patients with a tumor caushing chiasmal compression requiring surgery
9. Patients who have a known inherited syndrome as the cuase for hormone over
secretion
10. Patients with Cushing's syndrome due to ectopec ATCH secretion or
ATCH-independent Cushing's syndrome.
11. Patients who have undergone major surgery within 1 month prior to screening
12. Hypertensive patients with uncontrolled blood pressure defined as SBP >
180and / or DBP > 100
13. Diabetic patients with a poorly controlled diabetes as evidenced by HbA1c >
9%
14. Patients who are not biochemically euthyroid
15. Patients who have a history of: congestive heart failure (NYHA Class III or
IV) unstable angina, sustained ventricular tachycardia, clinically significant
bradycardia, advanced heart block, acute MI less than one year prior to study
entry, or clinically significant impairment in cardiovascular function.
16.Patients with moderate to severe renal impairment (estimated GFR < 60 mL/min
by the MDRD formula, or serum creatinine > 2.0 x ULN
17. Patients with liver disease such as cirrhosis, chronic active hepatitis, or
chronic persistenthepatitis, or patients with serum ALT/ASR > 3x ULN, or serum
bilirubin > 1.5 ULN.
18. Patients who have any current or prior medical condition that can interfere
with the conduct of the study or the evaluation of its results in the opinion
of the investigator or the sponsor's medical monitor
19. Patients who have a history of alcohol or drug abuse in the 6 month period
prior to the study treatment
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-004766-34-NL |
| ClinicalTrials.gov | NCT02180217 |
| CCMO | NL49292.078.14 |