[Management of Primary Ciliary Dyskinesia]. / Management der Primären Ciliären Dyskinesie.

Primary Ciliary Dyskinesia (PCD, MIM 242650) is a rare, hereditary multiorgan disease characterized by malfunction of motile cilia. Hallmark symptom is a chronic airway infection due to mucostasis leading to irreversible lung damage that may progress to respiratory failure. There is no cure for this genetic disease and evidence-based treatment is limited. Until recently, there were no randomized controlled trials performed in PCD, but this year, data of the first placebo-controlled trial on pharmacotherapy in PCD were published. This cornerstone in the management of PCD was decisive for reviewing currently used treatment strategies. This article is a consensus of patient representatives and clinicians, which are highly experienced in care of PCD-patients and provides an overview of the management of PCD. Treatments are mainly based on expert opinions, personal experiences, or are deduced from other lung diseases, notably cystic fibrosis (CF), COPD or bronchiectasis. Most strategies focus on routine airway clearance and treatment of recurrent respiratory tract infections. Non-respiratory symptoms are treated organ specific. To generate further evidence-based knowledge, other projects are under way, e. g. the International PCD-Registry. Participating in patient registries facilitates access to clinical and research studies and strengthens networks between centers. In addition, knowledge of genotype-specific course of the disease will offer the opportunity to further improve and individualize patient care.

Pre-activated antiviral innate immunity in the upper airways controls early SARS-CoV-2 infection in children.

Children have reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection rates and a substantially lower risk for developing severe coronavirus disease 2019 compared with adults. However, the molecular mechanisms underlying protection in younger age groups remain unknown. Here we characterize the single-cell transcriptional landscape in the upper airways of SARS-CoV-2-negative (n = 18) and age-matched SARS-CoV-2-positive (n = 24) children and corresponding samples from adults (n = 44), covering an age range of 4 weeks to 77 years. Children displayed higher basal expression of relevant pattern recognition receptors such as MDA5 (IFIH1) and RIG-I (DDX58) in upper airway epithelial cells, macrophages and dendritic cells, resulting in stronger innate antiviral responses upon SARS-CoV-2 infection than in adults. We further detected distinct immune cell subpopulations including KLRC1 (NKG2A)+ cytotoxic T cells and a CD8+ T cell population with a memory phenotype occurring predominantly in children. Our study provides evidence that the airway immune cells of children are primed for virus sensing, resulting in a stronger early innate antiviral response to SARS-CoV-2 infection than in adults.

The effects of roxatidine acetate on 24-hour intragastric acidity. Investigations in healthy volunteers and comparison with ranitidine and placebo.

In a series of double-blind randomised studies in normal volunteers with continuous intragastric pH monitoring, the effects of different dosage regimens of roxatidine acetate, a new H2-receptor antagonist, were compared with placebo and ranitidine. Roxatidine acetate 75 mg twice daily decreased median 24-hour gastric acidity from pH 1.6 to 3.2 and median nocturnal acidity from 1.5 to 3.0. Roxatidine acetate 150 mg at bedtime raised median 24-hour pH in the same 17 subjects to 2.4 and nocturnal pH to 5.9. In the second experiment, in 14 volunteers, roxatidine acetate 150 mg at bedtime was as effective as ranitidine 300 mg at night, raising median nocturnal pH from 1.4 to 6.65 compared to 6.7 for ranitidine. However, when drugs were taken after the evening meal (post cenam nocte; PCN) roxatidine acetate 150 mg was less potent than ranitidine 300 mg, with median night-time pH rising from 1.3 to 3.2 and 4.0, respectively, in 28 volunteers. Roxatidine acetate 300 mg PCN produced the greatest rise of pH, to 4.9, suggesting that the true potency ratio of the 2 drugs is between 1 and 2.

The effects of roxatidine acetate (HOE-760) on 24-hour intragastric acidity in healthy volunteers: comparison with ranitidine and placebo.

In a series of double-blind randomized studies in normal volunteers using continuous intragastric pH monitoring, the effects of different dosage regimens of roxatidine, a new H2-receptor antagonist, were compared with placebo and ranitidine. Roxatidine acetate, 75 mg twice daily, decreased median 24 h gastric acidity from pH 1.6 to 3.2 and median nocturnal acidity from 1.5 to 3.0. Roxatidine acetate, 150 mg at bedtime, raised median 24 pH of the same 17 subjects to 2.4 and nocturnal pH to 5.9. In another series of experiments, 150 mg roxatidine acetate at bedtime was as effective as ranitidine 300 mg nocte raising median nocturnal pH (14 volunteers) from 1.4 to 6.65 compared to 6.7, respectively. However, when drugs were taken after the evening meal (post cenam nocte, pcn) roxatidine acetate 150 mg was less potent than ranitidine 300 mg with median night-time pH rising from 1.3 to 3.2 and 4.0, respectively, in 28 volunteers. Roxatidine acetate 300 mg pcn raised the pH to 4.9 suggesting that roxatidine is 1-2 times as potent as ranitidine, on a milligram-for-milligram basis.

Comparison of ranitidine 300 mg twice daily, 300 mg at night and placebo on 24-hour intragastric acidity of duodenal ulcer patients.

Continuous measurement of 24-hour intragastric acidity was performed in 12 duodenal ulcer patients in remission during treatment with placebo, ranitidine 300 mg nocte and ranitidine 300 mg b.d. Median 24-hour acidity was 79.4 mmol litre-1 during placebo treatment; it decreased to 28.2 mmol litre-1 during treatment with ranitidine 300 mg nocte and to 3.6 mmol litre-1 during treatment with ranitidine 300 mg b.d. The two regimens decreased intragastric acidity to a similar degree during the night, but significantly greater inhibition of daytime and 24-hour acidity followed use of ranitidine 300 mg b.d.

[Statistical principles of "good clinical practice" in veterinary medicine--a position paper for planning, implementation and evaluation of empirical studies]. / Statistische Grundlagen von "Good Clinical Practice" in der Veterinärmedizin--ein Positionspapier zur Planung, Durchführung und Auswertung empirischer Untersuchungen.

The complexity of the design, conduct, analysis and evaluation of empirical studies necessitates a high degree of interdisciplinary collaboration in all areas of research. In order to make sure that no essential harmonisation is missed among the plenitude of processes, it has become common to provide direction on the essential operating procedures in so called "Good ... Practice" guidelines in recent years. In pharmaceutical research on human medicinal products guidelines on Good Clinical Practice have been an integral part of research and development in industry, academia, and the regulatory authorities for a long time. On the other hand, in the development and registration of pharmaceuticals for veterinary use such procedures are not yet established to this extent in Germany. Notwithstanding there being a lot of regulations on specialised subjects. This paper tries to summarise the current state of the discussion and to give an overview on the important points in the design, conduct, analysis and reporting of veterinary clinical studies mainly from an biometrical point of view.

[Biometrical methods for the proof of efficacy in regulatory submissions. Non-inferiority in clinical studies]. / Biometrische Verfahren zum Wirksamkeitsnachweis im Zulassungsverfahren Nicht-Unterlegenheit in klinischen Studien.

The increasing number of approved efficacious therapies for various indications raises the question of whether the inclusion of a placebo group is still justified. In addition, pharmaceutical companies and regulatory agencies acknowledge that it may be sufficient to prove that a new therapy is comparable to an approved reference therapy regarding efficacy and safety in some situations. This becomes especially striking for the approval to market a generic drug. Another, perhaps even more important example is the increasing resistance of bacteria which calls for new antibiotics based on new therapeutic principles without having the claim for better efficacy. In these situations, a comparable efficacy would constitute progress. In the present paper, we discuss the numerous methodological challenges and approaches to overcome these problems that occur when it is not possible or even not wanted to use the classic approach of a randomized placebo-controlled superiority trial. Here, the field of medical biometry, which has proved in the last 25 years to be an integral part of the development of new drugs, demonstrates its suitability as a flexible and scientifically based means to fulfil the requirements resulting from clinical practice. Starting from the fact that statistical methods are not able to prove "equality" of two treatments, "shifted" hypotheses are considered and their importance for the different study designs is discussed. We show how the classic hypotheses known from placebo-controlled clinical trials can be embedded in this concept. The implications of this approach for the analysis and interpretation of study results is further discussed. The relevant guidelines of the European and US regulatory agencies are taken into account.

Therapeutic equivalence investigations: statistical considerations.

Therapeutic equivalence studies still present problems to regulatory reviewers from many perspectives. This paper is intended to discuss some of these concerns from the statistical viewpoint. There are, however, also some newer approaches which may be particularly useful for the investigation of therapeutic equivalence.

Statistical considerations of FDA and CPMP rules for the investigation of new anti-bacterial products.

In this paper I investigate statistical properties of some guidance given by the FDA and by the CPMP on the planning, conduct and analysis of clinical trials with new anti-bacterial substances using an active control design. It is demonstrated that the non-inferiority margin proposed by the FDA has some undesirable features, and that the CPMP guidance may need further interpretation with respect to a statement that the non-inferiority margin may be smaller than 10 per cent for response rates >90 per cent. A new margin is proposed that combines the desirable properties from both the FDA and the CPMP guidance. It is also shown that the approximate unconditional tests that are in use in such trials are quite unreliable with respect to preserving the nominal type I error. Unconditional exact tests are presented as a remedy for this issue.

Controversies about sponsor initiated re-analyses of clinical trial data in the licensing process.

I present my experience with sponsor initiated re-analyses as a response to the regulatory agency's 'Mängelbericht', and the difficulties which arose from the fact that the regulatory agency was not involved in the plans for correcting mistakes or irregularities in the data and for the (re-)analysis of them. I also discuss the related problem when there are major discrepancies between the planned procedures laid down in the protocol and the actually applied procedures in the study report. I give examples for poor planning of a clinical study (sample size, statistical analysis, target variable(s)) and how this reduces the strength and value of a study. I introduce the phrase 'neutral party' as a means to resolve regulatory concerns about partiality in the sponsor's decisions, for example, introduction of new statistical models, different from the one planned, change in the order of the target variables, or dropping variables from the list of target variables.

An adaptive method for establishing a dose-response relationship.

A multistage sampling method is proposed in dose-response trials, where dose adaptions can be performed in the preplanned adaptive interim analyses. The overall test for proving a dose-response relationship is performed by Fisher's product criterion for the p-values from the separate tests of a dose effect in the disjoint samples at the different stages. Based on these p-values decision boundaries for early stopping with the rejection of the global null hypothesis of no existing dose-response relationship are introduced. The power of the adaptive two-stage procedure using a particular adaptation rule is compared with the power of the test for a linear trend under analysis of variance assumptions in extensive simulations. The bias in estimation is also quantified. This procedure could be used for establishing a dose-response relationship without including a placebo treatment.

[Antisecretory effect of the H2-histamine receptor antagonist ranitidine in water-soluble tablets and film-coated tablets. Results of a randomized, placebo-controlled crossover study in humans]. / Antisekretorische Wirksamkeit des H2-Histaminrezeptor-Antagonisten Ranitidin in Form von wasserlöslichen Tabletten und Filmtabletten. Ergebnisse einer randomisierten, Plazebo-kontrollierten Cross-over-Prüfung an Probanden.

This clinico-pharmacological trial aimed to prove equivalence between the known film-coated tablets of ranitidine (Sostril Filmtabletten) and the novel dispersible tablets for the preparation of a drinkable solution (Sostril Aquatabs) on a pharmacodynamic level. Therefore, the influence of single oral doses of the two ranitidine preparations (2 X 150 mg p.e.m. each) and placebo on the gastric hydrogen ion concentration was studied in 12 healthy volunteers using a randomized cross-over design. pH-values of the gastric juice were measured and recorded continuously for 24 h. Median pH-values for the entire study period were 2.20, 2.15 and 1.40 for dispersible tablets, filmcoated tablets and placebo, respectively. During the night-time median pH-values of 3.45 for both ranitidine preparations and 1.40 for placebo were calculated. From these results it can be concluded that the novel dispersible tablets are equivalent to the ranitidine filmcoated tablets with regard to their pharmacodynamic potency.

[The 4 second sleep spindle periodicity]. / Die 4 s Schlafspindelperiodik.

Polysomnographic EEGs were recorded from 12 adult volunteers between the ages of 20 and 50 years. They were given placebo, pentobarbital, carbromal, methaqualone, flunitrazepam, lormetazepam and triazolam. The visual evaluation was aimed at finding periodic sequences of centro-parietal sleep spindles at 13-15/s. Four consecutive spindles following each other regularly were defined as the shortest sequence. Placebo showed the following results: a considerable interindividual variance with 2 to 6 such sequences on the one hand and 25 on the other hand for each night. sequences with six periodically consecutive spindles dominated; the longest sequence contained 15 spindles. the inter-spindle distance was 4 seconds (m: 4.09; mean 4.14 s). All hypnotics caused an increase in periodic spindle sequences. Volunteers with a low tendency to have periodic spindle sequences remained at the lower end of the scale when taking hypnotics. Hypnotics increased the amount of longer spindle sequences, however, the average was still at sequences of 4-11 consecutive spindles. The inter-spindle distance became longer with all hypnotics; 4.34 s (carbromal) up to 4.58 s (flunitrazepam). Volunteers with a low tendency to have periodic spindle sequences showed shorter distances between spindles vice versa. Benzodiazepines do not reveal any characteristics due to their pharmacokinetic structure.

Contribution to the search for vigilance-indicative EEG variables. Results of a controlled, double-blind study with pyritinol in elderly patients with symptoms of mental dysfunction.

We used a clinical pharmacological model to test pyritinol versus placebo in patients with mental deficiency and a clinical diagnosis of beginning chronic brain syndrome. Following a two weeks' washout phase, 50 patients were randomly allocated to two treatment groups of 25 patients each, receiving either 200 mg pyritinol three times daily, or placebo under double-blind conditions. The treatment period lasted 8 weeks. To be included in the study, patients had to have at least 50% subvigil phases in the 15-min EEG resting recording. We define such behaviour as a neurophysiological disturbance of vigilance. Scores in the Benton test were to be 2 points below the expected value, and/or the NAF score was to be above a standard value attained in an old peoples' home (greater than or equal to 14). We used this clinical pharmacological model for an internal validation of our Vigilance Index (VI). According to our definition, the Vigilance Index should express vigilance in the sense of an optimalization of the neuronal system to enable this system to perform better. The delta F power and the alpha slow-wave index have been considered as vigilance-indicative variables in the EEG. We believe that vigilance can be better expressed by a multidimensional approach, which takes into account all EEG elements that express vigilance, such as the replacement of the occipital basic rhythm (e.g. alpha or beta rhythm) into slow waves, the lowering of the dominant occipital frequency (be it an alpha or beta frequency), the anteriorization of the basic rhythm in the occipital field to the frontal region.(ABSTRACT TRUNCATED AT 250 WORDS)

The COMSTAT algorithm for multimodal factor analysis: an improvement of Tucker's three-mode factor analysis method.

Three-mode factor analysis, as developed by Tucker in 1966, is a method for nonredundant representation of data arrays with three subscripts (e.g. observations classified according to persons by variables by conditions). Tucker , however, did not succeed in obtaining a least-squares solution for his model. We derive in this paper a necessary condition for a least-squares solution and construct an algorithm which improves any given initial solution in the least-squares sense. We show that this algorithm converges to a representation satisfying the necessary conditions for a least-squares solution. The method is in no way restricted to three dimensions, but can be applied to any multimodal data array.

Example for applying the COMSTAT multimodal factor analysis algorithm to EEG data to describe variance sources.

An example is given for the application of the COMSTAT algorithm for multimodal factor analysis to EEG power spectral data. The COMSTAT algorithm enlarges Tucker 's three-mode factor analysis to a multimodal one, and improves his algorithm by a least squares solution. The EEG power spectral data from 65 healthy subjects with an occipital rhythm between 8 and 12 Hz were taken. For demonstration purposes we selected three modes, which have been used by other authors: mode 1: 29 frequency classes, 1n of relative power, in delta f = 1.0-Hz steps between 1 and 30 Hz; mode 2: 16 segments, 40 s each, during the two situational vigilance conditions reaction time (RT) and resting (RS), and mode 3: 65 persons. The frequency mode could be described sufficiently by five factors which we called: delta F/alpha F1; nu F/alpha F2; beta F1/alpha F1; beta F2; beta F3. The factor-loading profiles were similar to those described earlier in independent data. Thus, in the three-mode model we obtained results comparable to those of two-mode models. In the level of 16 situational segments only two factors were extractable. They described the two situations RT, higher vigilance level, and RS, lower vigilance level. In order to demonstrate the changes in factor structure, if a two-mode model is enlarged by a third mode, we used two models for the description of personal (P) variance. When the matrix persons X segments (P X V) was taken, only two factors were extractable.(ABSTRACT TRUNCATED AT 250 WORDS)

COMSTAT rule for vigilance classification based on spontaneous EEG activity.

For the classification of sleep stages, international standards based on visual EEG analysis have been established and are in common use, although we are well aware of their limitations. Several authors have suggested different procedures for classifying the stages of vigilance during the waking stages. No universally accepted paradigm, however, has yet been developed. The proposed vigilance classification procedures are based either on visual or automatic analysis procedures. Even though the EEG activity and patterns that reflect vigilance changes have been identified and described as indicators of the state of alertness, opinion is divided on how these should be combined in a vigilance classification rule. Automatic methods, on the other hand, have up to now used only part of the information available, the relationship of which to vigilance indicators has only been partially explored. The COMSTAT (Dept. of Computation and Statistics, AFB-Arzneimittelforschung, Berlin, FRG) rule combines visual and automatic analysis procedures. Different vigilance-dependent EEG patterns, such as the proportion of occipital background rhythm under resting conditions and its replacement by either faster or slower waves, the frequency range of the occipital rhythm and the anteriorization phenomena, have been used as information for a latent class analysis (LCA5) with 5 classes (stages of vigilance). There is a high correlation between the results of the LCA5 with visual classification rules made by experts. Using a robust discriminant analysis function which takes into account prior probabilities of the classes, and with a linear cost function for misclassification, an automatic rule with power spectrum variables was fitted to the results of the LCA5. Reclassification and split-half classification showed a high overlap between LCA5 and automatic classification. The result of this procedure is a new vigilance classification rule that is based on an objective mathematical rationale for the combination of different vigilance-indicative EEG activities and patterns but which can be applied to power-spectral estimators in an automatic EEG analysis procedure.

Testing strategies in multi-dose experiments including active control.

Inferential test strategies for multi-arm trials are adapted or proposed for the special situation when more than one dose of a test treatment, placebo and active control(s) are compared. This includes between doses, dose-placebo and dose-active-control comparisons. The procedures refer to situations when detailed comparisons make sense only if the sensitivity of the trial has been shown, for example, if a dose-response relationship or a difference between active control and placebo has been established. Split strategies, hierarchical (assuming an order restriction among doses) or linked procedures are introduced. In linked procedures, equivalence to the active control will be established only if the dose is also shown to be effective as compared to placebo. All the inferential procedures control the experimentwise error rate in the strong sense for the respective sets of null hypotheses considered.

Clinical and statistical issues in therapeutic equivalence trials.

Absolute proof of efficacy can only be given by placebo controlled trials. It is, however, important to classify a drug within the spectrum of existing therapeutic alternatives and, where effective treatment is available, it may be imperative due to ethical considerations to demonstrate that one drug is as effective as another. The issue of therapeutic equivalence trials is discussed along the lines of the important items which should be defined in the protocol: a) the target parameter, which is the primary endpoint of the trial, b) the reference drug, which should be selected with respect to efficacy (superior to others), and safety (largest amount of data), c) the acceptance range, which depends on the primary endpoint, and its implication for the clinical endpoints of morbidity and mortality (the conventional acceptance range for bioequivalence trials does not apply), and d) the statistical procedures, which must take into consideration the unsuitability of the conventional power approach for confirming equivalence. In an equivalence trial, compared to those that are placebo-controlled, the proof that one drug is as effective as another relies much more upon the quality of conduct of the study according to Good Clinical Practice.