Randomised trial on episodic cluster headache with an angiotensin II receptor blocker

Introduction

Frequent attacks with unilateral excruciating pain accompanied by autonomic symptoms and signs are the hallmarks of cluster headache (CH) (1). Acute symptomatic treatment with subcutaneous sumatriptan or inhaled oxygen often provide good relief (2,3), but effective prophylactic medication is nevertheless highly desirable to reduce frequency of attacks (4). Unfortunately, the prophylactic treatment options in CH are few (5) (e.g. verapamil) and the effect is often poorly documented (Table 1). The lifetime prevalence is low (0.2–0.3%) (6), but for those affected the burden of disease is large (7), affecting quality of life, including ability to work and social relations.

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Table 1.

Prophylactic treatment studies on episodic cluster headache using ICHD criteria.

First author	Study drug	Year	CH type	N per- protocol (Total N included)	Weeks on treatment	Reduction in attacks during active treatment period	Reduction in attacks during placebo treatment period	Responders	Placebo-responders	Efficacy as stated in paper
Tronvik	Candesartan	2013	E	32 (40)	3 weeks	61%	38%	63%	46%	No (?)
Pageler17	Frovatriptan	2010	E	0 (11) b	2 weeks	5% a	38%	25%	67%	Insufficient data
El Amrani10	Valproate	2002	E + C	90 (96)	2 weeks	24% a	38%	50%	62%	No
Saper18	Civamide	2002	E	24 (28)	1 week	36% a	17%	NA	NA	Yes
Leone19	Verapamil	2000	E	30 (30)	2 weeks	45%	3%	80%	0%	Yes
Steiner20	Lithium	1997	E	27 (27)	1 week	NA c	NA c	62% d	43% d	No
Leone21	Melatonin	1996	E + C	20 (20)	2 weeks	21% e	7%	50% d	0%	Yes
Marks22	Capsaicin	1993	E + C	13(17)	1 week	NA f	NA f	NA	NA	Yes

Candesartan cilexetil (Atacand™), an angiotensin II receptor blocker, has been shown to prevent migraine attacks with few side effects (8). The present trial is the first study with the aim to evaluate candesartan as a prophylactic treatment in patients with episodic CH (ECH).

Methods

This was a multi-national, randomised, placebo-controlled, parallel study conducted at seven different centres, in Norway (n = five), Denmark (n = one) and Sweden (n = one) from 2004 to 2010. A flowchart for the study is provided in Figure 1. The trial was performed according to the guidelines for controlled trials of drugs in cluster headache (9) with one exception. In order to decrease the risk of spontaneous remissions before starting on medication, there was no medication-free baseline period. This was a recommendation from a previous large study on ECH (10).

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Figure 1.

Study flowchart.

Recruitment was performed at outpatient clinics and the diagnosis was verified by a neurologist. Inclusion criteria were ages 18–75 years, and a diagnosis of ECH was made according to the International Classification of Headache Disorders, second edition (ICHD-2) (1). In addition all patients should have had a period of at least one month with ECH previously, and no one should have had attacks for more than three weeks in the present cluster period before inclusion. Patients should also have been able to differentiate between CH attacks and other types of headache. Exclusion criteria were pregnancy, nursing or inability to use contraceptives in women; decreased hepatic or renal function; systolic blood pressure below 110 mmHg; hypersensitivity to active substance; previous history of angioneurotic oedema; use of daily cluster prophylactics in the four weeks prior to inclusion for lithium and two weeks for other medications; psychiatric illness preventing full participation in this study; heart condition; use of antihypertensives; use of specific attack treatment other than sumatriptan injections or oxygen; chronic CH; abuse of alcohol or narcotics; medication-overuse headache; and use of antipsychotic or antidepressive medication in the four weeks prior to inclusion.

Eligible patients underwent physical and neurological examinations. Medical history and demographics were obtained. Patients were instructed to keep headache diaries recording headache duration and severity, level of disability, presence of one or more autonomic symptoms (conjunctival injection, lacrimation, ptosis, miosis, eyelid oedema, nasal congestion, rhinorrhoea, forehead sweating), acute medication use and adverse events (free text).

After randomisation (computer-generated randomisation scheme), patients started immediately on either placebo (one tablet/day week 1 and two tablets/day weeks 2 and 3) or candesartan cilexetil 16  mg (one tablet/day) week 1 and 32 mg (two tablets/day) weeks 2 and 3. One week after randomisation all patients were contacted by phone, by the study nurse, to record side effects (checklist and open-ended questioning). After the medication period the participants continued to keep the diary for one week, using only acute medication. Active and placebo tablets, provided for the study by AstraZeneca, had the same size, weight, taste and appearance to ensure blinding. Patients were allowed to use sumatriptan injections or oxygen inhalation for acute attacks during the study. Randomisation and blinding were performed in accordance with the Consolidated Standards of Reporting Trials (CONSORT) statement (11).

Results

Recruitment had to be stopped after five years, at which time point 40 patients had been randomised. Thirty-two of them returned fully evaluable reports (candesartan = 19; placebo = 13). The distribution (19 versus 13) is precisely within one SD and is an example that exact balance is not easy to achieve in multicentre studies of small volumes.

The most plausible explanation outside this, however, may be an interruption process caused by expiration date of the study drugs. Of the eight patients not completing the study, five (candesartan = three, placebo = two) returned insufficient diary data, one (candesartan) was non-compliant with study drug intake, one (candesartan) was started on prednisolone therapy, and one (placebo) withdrew because of side effects. Seventeen (17) of 32 patients had previously tried one or more prophylactic medications for their CH. Background data on active and placebo groups, and on non-completers, are shown in Table 2.

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Table 2.

Baseline data.

	Completers		Non-completers
	Candesartan	Placebo	Candesartan	Placebo
N	19	13	5	3
Gender
Male	17	10	4	3
Female	2	3	1	0
Age	42 ± 10.1	41 ± 12.1	44 ± 12.1	52 ± 14.5
Weight (kg)	84 ± 10.7	81 ± 11.3	75 ± 5.8	75 ± 9.2
Height (cm)	181 ± 6.9	177 ± 7.0	178 ± 10.4	181 ± 2.9
Blood pressure a (mm Hg)
sys	136 (110, 160)	135 (115, 175)	144 (130, 150)	131 (115, 166)
Dia	85 (70, 100)	85 (70, 99)	85 (75, 101)	77 (70, 88)
Pulse a (bpm)	66 (48, 92)	71 (60, 84)	66 (60, 80)	80 (52, 81)
Non-cluster headache b (n)	3	5	2	2
Age at debut of cluster headache	25 ± 8.1	25 ± 9.7	27 ± 15.5	40 ± 14.1
Number of attacks per day a	2 (1, 15)	3 (1, 10)	2 (2, 4)	5 (3, 6)

Primary efficacy variable

Summary statistics (based on group sizes) on number of attacks for week 1 and 3 are provided in Table 3. The difference in attack numbers between week 1 and 3, when tested with a non-parametric test (Wilcoxon rank-sum test), was not statistically significant (p = 0.38). However, while all patients reported daily attacks during the first study week, only a subsample experienced attacks during week 3. The number of patients still reporting attacks (Figure 2) and the number of attacks reported (Figure 3) are shown to decline over time in both groups, but more so in the candesartan group (attack frequency reduction for candesartan 61% and placebo 38%). To take these properties of the data fully into account, the pre-specified statistical analysis on number of attacks was supplemented with an exact Mantel-Haenzel test of common Poisson relative risk (RR) over the whole treatment period (21 days). With this analysis the difference between the groups was highly significant (RR = 1.3; 95% confidence interval (CI) = 1.17–1.48; p < 0.0001).

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Figure 2.

Number of patients experiencing cluster headache each day in the 21-day treatment period (candesartan 16 mg week 1, 32 mg weeks 2 and 3).

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Figure 3.

Mean number of cluster attacks per day (candesartan 16 mg week 1, 32 mg weeks 2 and 3).

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Table 3.

Efficacy measures in study weeks 1 and 3.

	Week 1		Week 3		Difference Week 3–Week 1
	Candesartan (n = 19)	Placebo (n = 13)	Candesartan (n = 19)	Placebo (n = 13)	Candesartan (n = 19)	Placebo (n = 13)
Number of attacks (primary variable) c
Mean ± SD	14.3 ± 9.18	16.8 ± 14.08	5.6 ± 6.95	10.5 ± 11.30	−8.7 ± 9.12	−6.2 ± 8.71
Median (min, max)	11 (2, 37)	12 (3, 42)	2 (0, 21)	6 (0, 35)	−7 (−37,+3)	−6 (−24, +6)
Quartiles	9, 19	6, 23	0, 8	2, 16	−11, −3	−7, −1
Duration of attacks (hr) d
Mean ± SD	1.2 ± 0.37	1.8 ± 0.40	1.0 ± 0.45	1.0 ± 0.18	−0.2 ± 0.37	−0.7 ± 0.29
Median (min, max)	1.0 (0.9, 1.8)	1.6 (1.4, 2.4)	0.9 (0.4, 1.6)	1.0 (0.9, 1.5)	−0.2 (−0.9, 0.3)	−0.6 (−1.2, −0.5)
Number of oxygen or triptan treatments d
Mean ± SD	12.3 ± 9.74	12.8 ± 15.05	4.6 ± 6.04	8.0 ± 11.13	−7.7 ± 8.88	−4.8 ± 8.82
Median (min, max)	10 (0, 34)	7 (0, 41)	2 (0, 19)	2 (0, 35)	−6 (−34,+3)	−2 (−24,+6)
Autonomic symptoms d
Mean ± SD	12.9 ± 9.10	14.4 ± 13.23	4.7 ± 6.21	8.0 ± 10.89	−8.2 ± 8.09	−6.4 ± 9.42
Median (min, max)	11 (1, 31)	11 (1, 42)	2 (0, 18)	3 (0, 31)	−7 (−31, +4)	−4 (−21, +7)
Days with headache d	113	67	56	44	−57	−23
Mean ± SD	5.9 ± 1.58	5.2 ± 1.86	2.9 ± 2.91	3.4 ± 2.96	−3.0 ± 2.79	−1.8 ± 2.62
Median (min, max)	7 (2, 7)	6 (2, 7)	2 (0, 7)	3 (0, 7)	−2 (−7, 0)	−1 (−6, 2)
Hours with headache d	167	178	155	98	−12	−80
Mean ± SD	8.8 ± 7.13	13.7 ± 14.00	8.2 ± 15.61	7.5 ± 9.88	−0.6 ± 12.07	−6.2 ± 10.25
Median (min, max)	5.7 (0.8, 23.6)	11.0 (1.8, 53.1)	0.8 (0, 62.0)	3.1 (0, 31.7)	−2.2 (−20.4,+39.5)	−5.2 (−21.4,+16.1)
Severity indexa,d
Mean ± SD	2.7 ± 4.50	2.7 ± 1.74	2.4 ± 4.35	1.6 ± 1.29	−0.3 ± 2.32	−1.1 ± 2.34
Median (min, max)	1.6 (0.3, 20.9)	2.5 (0.3, 6.4)	0.8 (0, 16.8)	1.6 (0, 3.2)	−0.7 (−4.2,+7.2)	−0.5 (−6.4,+1.7)
Patient satisfaction week 3 d
Mean ± SD	NA	NA	5.3 ± 3.79	5.1 ± 3.84	NA	NA
Median (Q1, Q3) b	NA	NA	5 (1, 9)	5 (1, 9)	NA	NA

a

Subject mean duration of attack (hours) × level of disability (0–4). ^bTwenty-five per cent and 75% quartiles. (Minimum = 1, maximum = 10 in both treatment groups). ^cp > 0.05 for pre-specified ranking test and p < 0.0001 for post-hoc Poisson test. ^dp > 0.05.

Secondary efficacy variables

Data on secondary efficacy variables are provided in Table 3. Some of the variables described in the protocol were difficult to estimate without extensive assumptions outside the protocol. None of these were significant with the protocol-described statistical methods. Only the variables that could be assessed with a higher degree of certainty are provided in the paper. The rest of the data on outcomes (full list at clinicaltrials.gov) can be provided in full with information on limitations from the main author upon request. Numerically there is a larger reduction in the number of headache hours in the placebo group in week 3 compared to week 1 (not significant). The mean number of headache hours per patient is much lower for active substance (8.8 hours) than for placebo (13.7 hours). The percentage of patients with a 50% or more reduction in attack frequency in week 3 compared to week 1 was 63% for candesartan and 46% for placebo (p = 0.61, X² test).

The number of patients continuing to report attacks declined in both groups from the second treatment week, but at a higher rate in the candesartan group (Figure 2). At the end of the treatment period, nine of the 19 patients (47%) in the candesartan group and nine of the 13 patients (69%) in the placebo group were still reporting headache attacks (p = 0.29; 95% CI = 0.07–2.16, Fisher’s exact test). A Cox proportional hazards regression (HR) analysis was fitted to estimate the risk of experiencing cluster headache attacks over time, using candesartan or placebo. A non-significant difference (HR = 0.48; 95% CI = 0.20–1.18; p = 0.10), favouring candesartan, was observed for the entire 28-day study period (Figure 4).

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Figure 4.

Days to freedom from headache.

Adverse reactions are given in Table 4. A total of 14 patients reported adverse events (nine of 19 in the active group and five of 13 in the control group). OR 1.42; 95% CI = 0.28–7.80, p = 0.73. Orthostatic reactions or dizziness were reported by four patients in the candesartan group vs. none in the placebo group, and tiredness in eight vs. three instances.

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Table 4.

Number (n) of patients with adverse reactions. ^a

	Adverse event	Treatment group
		Candesartan	Placebo
		n = 19	n = 13
Completers (n = 32)	None	10	8
	Abdominal pain	1
	Common cold	1
	Cough	3	3
	Diarrhoea	1
	Dizziness	2
	Dyspnoea	1
	Feeling cold	1
	Influenza	1
	Joint stiffness	1
	Orthostatic symptoms	1
	Palpitations	1
	Running eyes	1
	Throat dryness	1
	Tiredness	5	1
	Unspecific skin sensation	2
Non-completers (n = eight)	None	1	1
	Asthenia	1
	Cough	2
	Dizziness	1
	Feeling cold	1
	Tiredness	3	2
	Unspecific skin sensation	1

a

A total of 14 patients reported adverse events (nine of 19 in the active group and five of 13 in the control group). Odds ratio (OR) 1.42; 95% confidence interval (CI) = 0.28–7.80, p = 0.73.

Discussion

In this first prospective, placebo-controlled, double-blind study on angiotensin receptor blockade in patients with CH, candesartan failed to reach statistical significance in the pre-specified statistical test, but was associated with a significant reduction in cluster attacks over the course of the study (p < 0.0001) and with a trend for shorter cluster period duration, when applying post-hoc statistical methods more appropriate for the studied variables.

Designing and performing studies on ECH is difficult (Table 1) because of both the rarity of the condition and the varying clinical expression among individuals within a cluster bout. However, it is nevertheless important to conduct studies on this condition as it is one of the worst pain conditions known, and with a significant impact on patients’ life (7).

The prophylactic treatment options available today are few and with limited efficacy, and only small studies (Table 1) are available with the exception of one relatively large study with a negative result. Most previous studies have reported effect as difference from baseline, defined as the period before start of the study drug, whereas we used the first week of drug treatment (half dose) as baseline. Since active treatment was given also during the baseline period, our calculations are more conservative than calculations using a placebo baseline. This has to be taken into account when conclusions on the trial are drawn. Figure 3 indicates that there is indeed a marked decline in attacks already in week 1 in the active group, not seen in the placebo group, and it may explain why the reduction in headache hours from weeks 1 to 3 was larger in the placebo group than in the candesartan group. The pre-planned statistics (week 1 vs. week 3) were therefore less suitable, and the post-hoc statistical method (13), which takes into account the development in attack frequency during the whole period from day 1, gives a better picture of the difference.

Lack of power may be another reason why the pre-specified analyses failed to show an impact of the active treatment. The study was calculated for 54 patients completing the trial period. However, despite a five-year recruitment period, we were able to include only 40 patients, and only 32 of them completed the study. Additional loss in power came from study group size imbalance, as 19 were randomised to candesartan and only 13 to placebo. Hence, the major limitations of the study were the lack of power and that the pre-planned statistical test was not optimal. Strengths of the study were the strict criteria for participation, inclusion of only ECH patients, and that it followed the guidelines for controlled trials of drugs in cluster headache (9). In addition it was a randomised, placebo-controlled, multicentre trial performed in three different countries.

The pathophysiological mechanism that could explain an effect of angiotensin II receptor blockers in CH is unknown. Several studies suggest that the posterior hypothalamus may play a part as a generator or modulator in trigeminal autonomic cephalalgias (14). The suprachiasmatic nuclei (SCN) of the hypothalamus are the main centres for the generation and regulation of circadian rhythms in mammals, and these are also thought to be important in the striking circadian pattern of CH attacks. SCN neurons synthesise a number of different neuropeptides, including angiotensin II (15). Circadian rhythms are generated in individual SCN neurons via transcription of so-called clock genes. In a peripheral tissue model, angiotensin II type 1 (AT₁) receptor activation by angiotensin II increases expression of the clock gene Per2, suggesting that this neuropeptide can regulate the molecular clock in the SCN as well (16). Theoretically, the angiotensin II receptor blocker candesartan may therefore exert an effect on these areas and mechanisms thought to be important in the pathophysiology of CH.

Based on the experience we have gained in this trial, we have some comments on how future CH studies may be planned and analysed. An essential aspect of ECH is its episodic (periodic) nature. A time-to-remission design offers several advantages and is probably the most efficient trial model for this condition. This study provides such an analysis. The major drawback is that a simple time to disappearance of attacks does not account for impact on frequency or severity and it is less useful in chronic CH, for which disappearance of attacks may not be a realistic goal. Another important aspect of CH is that the attacks occur over a period of time; i.e. as counts over a unit, which is relevant for both ECH and chronic CH. This count will frequently be zero or missing, making use of classical non-parametric tests sub-optimal. Cases with missing data will be lost, giving those who fail to provide data with a high impact, and a high number of zero values results in many ties and loss of the non-parametric characteristics. To evaluate the attack rate in smaller CH trials, Poisson-based methods, which we used in the post-hoc analysis, are probably preferable.

In a previous study (10) the use of run-in periods was advised against in CH studies because the short duration of the periods may not allow for sufficiently long treatment periods. Use of a baseline period with active medication, as we used in this study, is clearly not advisable since medication may have an effect from early in the treatment period. One should therefore use a design not requiring a baseline period at all.

Recruiting enough ECH patients and difficulty with including them immediately after the start of a cluster period poses a challenge for the researcher as reflected in the small clinical trials available. We recommend that an international research consortium on CH be established so that future trials can be expected to have sufficient power and be executed during a shorter period.

Conclusion

This was a negative study, but lack of power and statistics less suitable to find true differences with temporal changes made it impossible to make decisive conclusions on the efficacy of candesartan in ECH prophylaxis. Post-hoc statistics suitable to describe the temporal changes in CH did, however, indicate a possible therapeutic effect, so future studies on candesartan, perhaps also including patients with chronic CH, may be justified.

Clinical implications

Candesartan was not significantly different from placebo in episodic cluster headache.