CandeSpartan Study. Candesartan Spanish Response-prediction and Tolerability Study
CandeSpartan Study. Candesartan Spanish Response-prediction and Tolerability Study
Observational, prospective, descriptive, open study on response predictors and tolerability
 of Candesartan in patients >18 years with episodic or chronic migraine with prior failure of
 three or more preventive drugs. Patients will receive Candesartan the same manner and
 intensity if they were not enrolled in the study. Vital signs, clinical variables and adverse
 events will be monitored.

 Primary endpoint will be to determine demographic and clinical factors associated with a 50%
 reduction in the frequency of headache days per month between weeks 20 and 24 compared with
 baseline.
CandeSpartan Study Candesartan Spanish Response-prediction and Tolerability study

 Observational study on response predictors and tolerability of Candesartan in usual clinical
 practice

 INTRODUCTION:

 Migraine is a neurological disease with a prevalence of 14% of the population 1, 2. It is the
 second most disabling disease in terms of years of life lived with disability, especially in
 the age group between 15 and 49 years3. Migraine is also the headache the most frequently
 seen in neurology consultations and headache units4.

 Since the 1970s, numerous preventive drugs have been developed. One of the problems is that
 many of these drugs come from other indications, such as depression, epilepsy or
 hypertension5. Nowadays, clinical practice guidelines base the indication mainly on the level
 of evidence6, which, given the age and scarcity of these studies, is limited. Although the
 new drugs are based on clinical trials according to the current methodology, they are
 unlikely to be indicated in patients who have not tried any preventive treatment.

 Candesartan is an angiotensin-2 receptor antagonist drug that has shown efficacy in episodic
 migraine mainly in two clinical trials compared to placebo, using a 16 mg daily dose. The
 first study showed a monthly headache days reduction of 4.9 days of (standard deviation 10.6)
 in episodic migraine patients that had previously failed to none or one preventive, with 2-6
 episodes of headache per month at baseline7. The second study had three arms, including
 propranolol and placebo showing a montly headache days reduction of -2.91 days (standard
 deviation 1.06) and showing no-inferiority with respect to propranolol8.

 Spanish official headache guidelines recommend Candesartan use in patients with migraine with
 and without aura, particularly if they have hypertension or comorbid depression6. In some
 international prestige centers, it is the first choice drug. In habitual clinical practice,
 one aspect that limits its use is tolerability, being frequent the presence of hypotension
 and dizziness, even at the dose of 8mg, frequently used in our environment9. In the studies
 carried out, there were adverse effects in 45-50% of the patients and in 10% of patients was
 a reason for treatment discontinuation 7, 8.

 The aim of our study is to evaluate which clinical factors are associated with a better
 therapeutic response or a worse tolerability in usual clinical practice.

 Hypothesis The therapeutic response and tolerability to candesartan may be influenced by
 individual factors or related to the evolution of migraine.

 PATIENTS AND METHODS:

 Design:

 Multicentric, prospective, observational, descriptive, open, study of the response and
 tolerability predictors of candesartan in migraine patients.

 Eligibility:

 Inclusion criteria:

 Diagnosis of migraine (episodic or chronic) according to the International Classification of
 headache Disorders (ICHD), 3rd version, criteria10.

 Being treated with Candesartan under the criteria of the physician and according to local
 guidelines.

 Age >18 years. More than 4 days of headache per month in the preceding 3 months. More than 1
 year of migraine evolution. Beginning of migraine before the age of 50. Ability to provide
 informed consent.

 Exclusion criteria:

 Previous failure of three or more preventive drugs in accordance with the definition provided
 below.

 Concomitant use of another preventive drug or use of it in less than 5-half lives of the
 drug.

 History of another active primary headache with a periodicity considered frequent according
 to the International Classification of Headache disorders, that is, more than 10 days per
 month at the time of screening or the basal period.

 Continuous or daily headache in the month prior to inclusion in the study. Pregnancy or
 breastfeeding. Any relevant cardiovascular conditions. Kidney diseases. Hyperkaliemia. Use of
 another concomitant preventive. Previous use of candesartan. Current use of another
 Angiotensin Conversing Enzime Inhibitor or Angiotensin-II receptor antagonist.

 Alcoholism or drug use.

 Concomitant treatment:

 The study will not interfere in the current practice, participants will receive the
 candesartan in the same manner and intensity if they were not enrolled in the study.

 Patients will be allowed to use their usual symptomatic treatment as usual. The number of
 days of symptomatic treatment and the number of use of triptans will be reflected.

 The concomitant drugs with potential use as a preventive according to National Clinical
 Practice guidelines (gabapentin, pregabalin, tricyclic antidepressants, duloxetine, valproic
 acid, phenytoin, lamotrigine, topiramate, botulinum toxin, anti-CGRP antibodies,
 beta-blockers, lisinopril) will not be permitted.

 Treatment failure shall be defined as insufficient efficacy at a sufficient dose and for an
 adequate duration or withdrawal due to adverse effects of a drug present in the national
 headache guidelines.

 Intervention and visits:

 The visits will be carried out in the Headache Units of the participating centers. At the
 baseline visit, investigators will review that patients meet all inclusion criteria and none
 exclusion criteria. In accordance with the Good Clinical Practice guidelines12, a clear
 explanation will be given of the objective of the study, the role of the participant and the
 complete absence of risks that the study pose, due to the observational nature. The
 participant will be provided with a contact telephone number where he or she can contact in
 the event of an incident that want to refer to the investigators. The informed consent will
 be signed and a copy given to the participant.

 During the initial visit, the monthly headache days at baseline will be gathered, including
 the number of days of intense pain, the number of days of taking symptomatic medication, the
 number of days of taking triptans and the number of visits to the emergency department. A
 number of demographic and clinical variables (described below) will be reviewed. The patient
 will be asked to make a prospective record of his or her days of headache as well as the
 intensity of headache and the use of medication in a standardized diary (appendix) for
 thirty-six weeks. The presence of possible adverse effects will be detailed. The patient will
 be evaluated and both basal blood pressure and heart rate will be measured. Headache Impact
 Test (HIT-6) and Hospital Anxiety and Depression Scale (HADS), Allodynia Symptom Checklist
 (ASC-12) scales will be administered.

 Administration of candesartan:

 Participants will receive candesartan in the same manner and intensity as if they would not
 be enrolled in the study, according to the Spanish national guidelines.

 A follow up visit will be done at week 12 to analyze response to candesartan and the
 possibility of adverse effects. Physicians will modify candesartan dose according to their
 criteria and the local guidelines. Treatment response will be analyzed during the third
 visit, at week 24.

 Study variables:

 Demographic variables:

 Sex, current age, age of onset, type of migraine (episodic/chronic), months of evolution of
 chronic migraine, weight, height, overweight (determined according to the CUN-BAE scale).

 Clinical variables:

 Presence of aura, bilateral or unilateral predominance, headache intensity (0-10 verbal
 analogue scale), presence of allodynia (ASC-12 scale), prior history of psychiatric
 comorbidity (anxiety, depression), impact of headache (HIT-6 scale score).

 Headache days per month, intense headache days per month, emergency department visits per
 month, medication days per month, triptan days per month.

 Previous preventive drugs: drug, maximum dose, time of use, presence of adverse effects,
 response rate (0-30, 30-50, 50-75 or 75-100%).

 Blood pressure (mmHg), heart rate (beats per minute).

 Safety variables:

 Dizziness, tiredness, reduced physical capacity, nausea, constipation, sleep disturbance,
 sexual dysfunction and paresthesias.

 Monitoring of adverse effects:

 The patient will spontaneously report the presence of an adverse effect and will also be
 asked through a structured questionnaire during each visit (appendix). The severity of the
 adverse effect and the relationship with the study drug with the drug will be detailed and
 described by the investigator.

 Follow-up:

 Each patient will use a prospective monthly calendar that will facilitate a correct recording
 of the characteristics of the headache, including frequency, intensity, need of symptomatic
 drugs and presence of any adverse events.

 During each visit, presence of adverse effects such as pain, sensation of contracture or
 discomfort will be systematically evaluated. Spontaneous reporting of adverse effects will be
 allowed and also direct questions will be asked.

 OBJECTIVES:

 Main objective11:

 To determine which demographic or clinical variables present at baseline are associated with
 a 50% reduction in the frequency of headache days per month between weeks 20 to 24 compared
 with baseline in a regression analysis.

 Secondary objectives:

 To determine which demographic and clinical variables present at baseline are associated with
 a greater reduction in the frequency of headache days per month between weeks 20 to 24
 compared with baseline in a regression analysis.

 To determine frequency and type of adverse effects related with candesartan through study
 completion, an average of 24 weeks.

 To evaluate percentage of patients that discontinues candesartan due to adverse events
 through study completion, an average of 24 weeks.

 To evaluate percentage of patients that present a 50% response rate to candesartan in
 headache day reduction evaluated in the period between weeks 20 to 24 compared with baseline.

 To evaluate percentage of patients that present a 50% response rate to candesartan in
 headache day reduction evaluated in the period between weeks 8 to 12 compared with baseline.

 To evaluate percentage of patients that present a 30% response rate to candesartan in
 headache day reduction evaluated in the period between weeks 20 to 24 compared with baseline.

 To evaluate percentage of patients that present a 30% response rate to candesartan in
 headache day reduction evaluated in the period between weeks 8 to 12 compared with baseline.

 To evaluate percentage of patients that present a 75% response rate to candesartan in
 headache day reduction evaluated in the period between weeks 20 to 24 compared with baseline.

 To evaluate percentage of patients that present a 75% response rate to candesartan in
 headache day reduction evaluated in the period between weeks 8 to 12 compared with baseline.

 To evaluate percentage of patients that present a 100% response rate to candesartan in
 headache day reduction evaluated in the period between weeks 20 to 24 compared with baseline.

 To evaluate percentage of patients that present a 100% response rate to candesartan in
 headache day reduction evaluated in the period between weeks 8 to 12 compared with baseline.

 To evaluate headache days reduction in the period between weeks 20 to 24 compared with
 baseline.

 To evaluate headache days reduction in the period between weeks 8 to 12 compared with
 baseline.

 To evaluate intense headache days reduction in the period between weeks 20 to 24 compared
 with baseline.

 To evaluate intense headache days reduction in the period between weeks 8 to 12 compared with
 baseline.

 To evaluate acute medication days reduction in the period between weeks 20 to 24 compared
 with baseline.

 To evaluate acute medication days reduction in the period between weeks 8 to 12 compared with
 baseline.

 To evaluate change in HIT-6 scale in the period between weeks 20 to 24 compared with
 baseline.

 To evaluate change in HIT-6 scale in the period between weeks 8 to 12 compared with baseline.

 To evaluate change in HADS scale in the period between weeks 20 to 24 compared with baseline.

 To evaluate change in HADS scale in the period between weeks 8 to 12 compared with baseline.

 To evaluate change in heart rate (in beats per minute) in the period between weeks 20 to 24
 compared with baseline.

 To evaluate change in heart rate (in beats per minute) in the period between weeks 8 to 12
 compared with baseline.

 To evaluate change in systolic blood pressure (in mmHg) in the period between weeks 20 to 24
 compared with baseline.

 To evaluate change in systolic blood pressure (in mmHg) in the period between weeks 8 to 12
 compared with baseline.

 To evaluate change in diastolic blood pressure (in mmHg) in the period between weeks 20 to 24
 compared with baseline.

 To evaluate change in diastolic blood pressure (in mmHg) in the period between weeks 8 to 12
 compared with baseline.

 STUDY DESIGN

 Sample size:

 For calculation of sample size we used the combined data from both studies, in which, through
 analysis by intention to treat, the 50% response rate in the group treated with candesartan
 was 18/57 and 24/66, for a combined response rate of 42/123=34.1%. In the placebo group the
 50% response rate in the placebo group was 1/57 and 14/64, for a combined ratio of
 15/121=12.4%.

 Randomization:

 This is an open, not controlled with placebo study.

 Stratification:

 There will be no stratification of patients. Regression analysis will be performed to
 evaluate factors associated with better response or worse tolerability.

 Statistical aspects:

 An anonymous database will be created in which the identity of the patient will be
 dissociated from the rest of the data. SPSS statistics package will be used for statistical
 analysis. Analyses will be performed both by intention to treat and per protocol, the primary
 objective being determined by intention to treat.

 The main variable will be calculated by evaluating percentage of patients in whom the number
 of headache days per month, evaluated between weeks 20-24, is at least 50% lower than the
 number of headache days per month in the baseline period, before the use of candesartan.

 Logistic regression analysis and linear regression will be performed depending on the type of
 variable and those associated variables with a value of p<0.05 will be selected. In addition,
 a multivariate regression analysis will be carried out in which all variables with a p<0.015
 will be included and a second analysis will be carried out in which the number of days of
 reduction with respect to the baseline situation between weeks 20 and 24 will be used as a
 variant.

 Factors associated with the presence of adverse effects will be analyzed by logistic or
 linear regression analysis. 30%, 75% and 100% response rate analysis will also be performed.

 To evaluate the reduction in days of pain, the mean number of days of pain between weeks
 20-24 and the baseline period will be compared. It will be evaluated if the distribution is
 normal using the Kolmogorov-Smirnov test and if appropriate, the Student t test will be
 performed for paired samples; using the Mann-Whitney U test in case the distribution is not
 normal. The analysis will be repeated for the period between weeks 8-12 and weeks 32-36. The
 same analysis will also be done to determine the change in the average number of days of
 severe pain and days of use of symptomatic medication. The mean score on the HIT-6 and HADS
 scales over the same periods and the change in heart rate and blood pressure will also be
 compared. The Bonferroni method will be used to correct for multiple comparisons. In the
 comparison of qualitative variables, the Chi-square test or the exact Fisher test in
 non-parametric variables will be used. An intermediate analysis will be carried out when 50%
 of the patients have been recruited.

 The management of lost data will be done by imputation in a worse-case scenario. Missing days
 will be considered days with pain and treatment.

 Ethical and legal aspects:

 Eligible patients will be exposed to the possibility of participating in the study and if
 they accept, they will be explained in detail the objective, the procedure and what their
 participation consists of. If they accept, they must sign an informed consent12. In the event
 of refusing participation or revoking consent, patients may continue their usual treatment
 and care process without any modification or conditions. They will be free to refuse to
 participate in the study or to suspend their collaboration whenever they wish, with no impact
 on their future medical care.

 An anonymized database will be created and stored in the hospital of the principal
 investigator with the list of participants and personal data dissociated and separated from
 it.
Inclusion criteria:

 Diagnosis of migraine (episodic or chronic) according to the International Classification
 of headache Disorders (ICHD), 3rd version, criteria10.

 Being treated with Candesartan under the criteria of the physician and according to local
 guidelines.

 Age >18 years. More than 4 days of headache per month in the preceding 3 months. More than
 1 year of migraine evolution. Beginning of migraine before the age of 50. Ability to
 provide informed consent.

 Exclusion criteria:

 Previous failure of three or more preventive drugs in accordance with the definition
 provided below.

 Concomitant use of another preventive drug or use of it in less than 5-half lives of the
 drug.

 History of another active primary headache with a periodicity considered frequent according
 to the International Classification of Headache disorders, that is, more than 10 days per
 month at the time of screening or the basal period.

 Continuous or daily headache in the month prior to inclusion in the study. Pregnancy or
 breastfeeding. Any relevant cardiovascular conditions. Kidney diseases. Hyperkaliemia. Use
 of another concomitant preventive. Previous use of candesartan. Current use of another
 Angiotensin Conversing Enzime Inhibitor or Angiotensin-II receptor antagonist.

 Alcoholism or drug use.

 Concomitant treatment:

 The study will not interfere in the current practice, participants will receive the
 candesartan in the same manner and intensity if they were not enrolled in the study.

 Patients will be allowed to use their usual symptomatic treatment as usual. The number of
 days of symptomatic treatment and the number of use of triptans will be reflected.

 The concomitant drugs with potential use as a preventive according to National Clinical
 Practice guidelines (gabapentin, pregabalin, tricyclic antidepressants, duloxetine,
 valproic acid, phenytoin, lamotrigine, topiramate, botulinum toxin, anti-CGRP antibodies,
 beta-blockers, lisinopril) will not be permitted.

 Treatment failure shall be defined as insufficient efficacy at a sufficient dose and for an
 adequate duration or withdrawal due to adverse effects of a drug present in the national
 headache guidelines.