THALI-HHT

Fondazione IRCCS Policlinico San Matteo

Viale Golgi 19, Pavia, Italy, 27100

Struttura di Medicina Generale III, Fondazione IRCCS Policlinico San Matteo, 0039 0382 502169, r.invernizzi@smatteo.pv.it

Struttura di Medicina Generale III, Fondazione IRCCS Policlinico San Matteo, 0039 0382 502169, r.invernizzi@smatteo.pv.it

No

No

No

Final

15 Feb 2017

Yes

11 Oct 2016

Yes

11 Oct 2016

No

To assess the clinical effects of thalidomide therapy on the severity of epistaxis in subjects with HHT who are refractory to standard therapies.

This study was conducted in agreement with the Declaration of Helsinki, which provides the greatest protection of the patient. The protocol has been written, and the study was conducted according to the ICH Harmonized Tripartite Guideline for Good Clinical Practice) (EMEA 2006). The protocol and the informed consent were approved by the local Ethics Committee. Any amendment of the protocol and/or consent form has been approved by the Ethics Committee. The name of the patient was not recorded on case report forms. A sequential identification number was attributed to each patient registered in the trial. This number identified the patient and had to be included on all case report forms. In order to avoid identification errors, patient’s initials (maximum of 4 letters) and date of birth were also reported on the case report forms. Prior to entering the study, patients were informed of the aims of the study, the nature of the study drug and the study procedures, the possible adverse events, the strict confidentiality of their data, but that their medical records could be reviewed for trial purposes by authorized individuals other than their treating physician. It was emphasized that the participation was voluntary and that the patient was allowed to refuse further participation in the protocol whenever he/she wanted. This would not prejudice the patient’s subsequent care. Documented informed consent was obtained for all patients included in the study before they were registered. The written informed consent form was signed and personally dated by the patient or by the patient’s legally acceptable representative and by the investigator. The Investigator agreed, by signing the protocol, to adhere to the instructions and procedures described in it and thereby to adhere to the principles of Good Clinical Practice.

01 Dec 2011

No

No

Italy: 31

31

31

0

0

0

0

0

0

11

20

0

Overall study (overall period)

Not applicable

Thalidomide

Capsule

Oral use

Eligible patients received thalidomide at a starting dose of 50 mg/day by mouth at bedtime for four weeks. In the event of no response, thalidomide dosage was progressively increased by 50 mg/day every four weeks until complete or partial response, to a maximum expected dose of 200 mg/day. Then, treatment was continued as follows: eight additional weeks after the achievement of complete response, 16 additional weeks after the achievement of partial response, 24 weeks in case of no response. A maximum dose of 100 mg/day was used in patients older than 74 years. The duration of the induction treatment was then from 12 to 28 weeks, depending on the effective dose for response achievement.

Overall study

Thalidomide

The primary end point was computed as percentage of patients showing a reduction to grade 1-2 at least in one of the epistaxis parameters (frequency, intensity, duration). The difference between baseline scores and frequency, intensity, and duration scores evaluated at each time point during treatment was computed. If any of these was more than zero, the patient was considered as responder. A complete responder was defined as a patient with all three epistaxis scores equal zero. Reduction in the severity of any bleeding parameter less than complete response did represent partial response. Both complete and partial response had to be maintained for at least four weeks. Failure to achieve at least a partial response was defined as no response, whereas relapse after complete or partial response was defined as the regression from complete response to any other degree of response or return from partial response to pretreatment severity of bleeding parameters.

Primary

Each 4-week period. After response achievement, patients were treated for 8 to16 additional weeks. The duration of the induction treatment was then from 12 to 28 weeks, depending on the effective dose for response achievement.

Thalidomide treatment removed or greatly reduced the need for transfusions with a maximum decrease of 1.77 (95% CI 0.70-2.84) transfused red blood cell units per month. Twenty (87%, 95% CI 66-97) of the 23 patients who were dependent on transfusions became transfusion independent.

Secondary

The mean number of blood transfusions was calculated during the study period together with a Poisson 95% CI, and the change in the number of transfused units per month was analysed with a repeated measures negative binomial regression model.

Twenty-five patients (81%) obtained remission with 50 mg/day of thalidomide, after 4 weeks, five (16.1%) with 100 mg/day following 8 weeks, and one (3.2%) with 150 mg/day after 12 weeks of treatment. Time to response was associated with dose of thalidomide.

Secondary

The number and percent of responders at 4, 8, 12, 16, 20, 24 and 28 weeks and binomial 95% CI was computed. The minimum dose of the drug that reduces bleeding was summarized as number and percent of patients for each dosage (50, 100, 150 and 200 mg)

Relapse-free survival was described and plotted with the Kaplan Meier method. Thirty patients completed the treatment. A patient, who achieved partial remission after eight weeks of treatment at a dose of 100 mg/day thalidomide, noticed progressive worsening of epistaxis in the following weeks and underwent surgical treatment. An 80-year-old male patient suddenly died a month after the end of treatment for unknown reasons. A relationship with therapy could not be completely excluded, although no side effects had been recorded during treatment. At a median follow-up of 14.1 months after the end of therapy, 8 (27.59%) patients maintained remission, whereas 21 patients (72.41%) relapsed with a median relapse-free survival of 7.0 months (95% CI 6.1-9.6). We detected no association between clinical features (age, sex, epistaxis severity) and time to response, response duration or toxicity.

Secondary

The observation began at the date of therapy termination and stopped at the date of relapse for patients relapsing or at the end of the study follow-up otherwise

Treatment significantly increased patients' hemoglobin concentrations (p=0.00011), with a maximum increase of 2.27 g/dL (95% CI 1.13-33.42).

Secondary

The mean Hb level (SD) was computed at each 4-week period. The difference between baseline and end-of-treatment Hb levels were compared with the paired Student t test. A regression model for repeated measures was fitted to describe changes over time.

We assessed toxic effects every 4 weeks during treatment. The number (%) of adverse events for each grade of toxicity was tabulated for each system at each time point

Patients had only non-serious, grade 1, adverse effects during treatment, the most common of which were constipation and drowsiness. Thalidomide did not need to be discontinued for any patient

4.0

Thalidomide 4 weeks

Thalidomide 8 weeks

Thalidomide 12 weeks

Thalidomide 16 weeks

Thalidomide 20 weeks

Thalidomide 24 weeks

Thalidomide 28 weeks